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Gastrointestinal basidiobolomycosis: An emerging mycosis difficult to diagnose but curable. Case report and review of the literature
Accepted Manuscript Gastrointestinal basidiobolomycosis: An emerging mycosis difficult to diagnose but curable. Case report and review of the literature Maria Diletta Pezzani, Valentina Di Cristo, Carlo Parravicini, Angelica Sonzogni, Marco Franzetti, Salvatore Sollima, Mario Corbellino, Massimo Galli, Laura Milazzo, Spinello Antinori PII:
S1477-8939(19)30009-2
DOI:
https://doi.org/10.1016/j.tmaid.2019.01.013
Reference:
TMAID 1378
To appear in:
Travel Medicine and Infectious Disease
Received Date: 21 June 2018 Revised Date:
18 December 2018
Accepted Date: 16 January 2019
Please cite this article as: Pezzani MD, Di Cristo V, Parravicini C, Sonzogni A, Franzetti M, Sollima S, Corbellino M, Galli M, Milazzo L, Antinori S, Gastrointestinal basidiobolomycosis: An emerging mycosis difficult to diagnose but curable. Case report and review of the literature, Travel Medicine and Infectious Disease (2019), doi: https://doi.org/10.1016/j.tmaid.2019.01.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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TMAID-D-18-00147R1
but curable. Case report and review of the literature
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Gastrointestinal basidiobolomycosis: an emerging mycosis difficult to diagnose
Maria Diletta Pezzani 1*§, Valentina Di Cristo 1*, Carlo Parravicini 2, Angelica Sonzogni 3, Marco Franzetti 4^, Salvatore Sollima 4, Mario Corbellino 4, Massimo Galli 1,4, Laura Milazzo 4 , Spinello
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Antinori 1,4
Department of Biomedical and Clinical Sciences “Luigi Sacco”, University of Milano, Italy;
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Institute of Pathology, Luigi Sacco Hospital, Milano, Italy; 3Division of Pathology, Istituto
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Europeo di Oncologia, Milano, Italy; 4 III Division of Infectious Diseases, ASST Fatebenefratelli
Correspondence to : Prof Spinello Antinori
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Sacco, Ospedale L Sacco, Milano, Italy
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Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milano, Italy
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Tel 00390250319765
Email: [email protected] Key words : Basidiobolomycosis ; gastrointestinal infection ; Italy ; emerging mycosis * MDP and VDC contributed equally to this work § Present address. Dipartimento di Diagnostica e Sanità Pubblica, Università di Verona ^ Present address: Medicine Department, Division of Infectious Diseases, A Manzoni Hospital, ASST Lecco
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ACCEPTED MANUSCRIPT Abstract Background: Gastrointestinal basidiobolomycosis (GIB) is a rare mycosis affecting almost exclusively immunocompetent subjects Methods: We describe a case of GIB caused by Basidiobolus ranarum in a 25-year-old Italian
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immunocompetent man resident in Ireland who presented a 2-month history of epigastric pain. Suspecting colon cancer he underwent a right hemicolectomy subsequently leading to a diagnosis of GIB by means of molecular biology. After surgery a 9-month therapy with itraconazole was
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employed with a good outcome. A review of medical literature regarding GIB cases published in the period 1964-2017 is presented.
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Results: One-hundred and two cases of GIB were included in this analysis. The disease was observed predominantly in male gender (74.5%) and children (41.2%). Abdominal pain was the single most common complaint (86.3%) followed by fever (40.2%) and evidence of an abdominal mass (30.4%). Peripheral blood eosinophilia was detected in 85.7% of cases. Most of the patients
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were diagnosed in Saudi Arabia (37.2%) followed by USA (21.6%) and Iran (20.6%). Surgery plus antifungal therapy was employed in the majority of patients (77.5%). An unfavourable outcome was documented globally in 18.6% of patients
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Conclusions: GIB seems to be an emerging intestinal mycosis among immunocompetent patients
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living in the Middle East and Arizona.
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1. Introduction Basidiobolus ranarum was initially described in 1886 as a fungus cultured from frogs and two years later cultured from their intestinal contents and excreta [1]. It was first isolated in 1955 from
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decayed leaves in the United States and subsequently from soil and decaying vegetation from throughout the world [2-5]. It is actually classified in the phylum Entomophthoromycota that includes one of the largest groups of early-diverging terrestrial fungi previously classified in the
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phylum Zygomycota (Table 1) [6,7]. B. ranarum belongs to the class Basidiobolomycetes which includes a single order and family and it is a commensal in the gut of amphibians (frogs, toads), fish
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, reptiles and insectivorous bats [7]. B. haptosporus, B. heterosporos and B. meristosporos have been considered in the past as synonyms of the species B. ranarum [8]. Human disease caused by Basidiobolus was first described as a skin and subcutaneous indolent and slowly progressing infection, affecting the limbs, trunk and buttocks of young males residing in tropical and subtropical
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regions [9-11]. The exact mode of transmission of the fungus has not yet been characterised but in the case of subcutaneous disease, it has been attributed to the more frequent habit (by males) of using decaying plant leaves as toilet paper after defecating in the open or otherwise via minor skin
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trauma and insect bites. However, it remains puzzling how the fungus is introduced into the host’s gastrointestinal tract, thus resulting in gastrointestinal basidiobolomycosis (GIB). It has been
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suggested that ingestion of soil, animal faeces or food contaminated by either might be responsible , explaining the highest number of cases observed among children. The first case of GIB was probably reported in 1964 as an autopsy diagnosis in a 6-year old children from Nigeria who had also subcutaneous lesions [4]. However, Brazilian authors were the first who recognised GIB as a distinct clinical entity affecting immunocompetent individuals [12]. Although considered an extremely rare disease, GIB seems to be an emerging fungal infection in Saudi Arabia, Iran, Iraq and Arizona in the United States of America. We report here a case of GIB observed in a young immunocompetent Italian patient together with a review of the literature. 3
ACCEPTED MANUSCRIPT 2. Materials and methods Definitions We defined a confirmed case of GIB on the basis of either the characteristic histopathologic appearance of the fungus in tissue biopsy or from surgical specimens obtained from gastrointestinal
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organs (i.e., stomach, small intestine, colon, rectum, liver, gallbladder, pancreas) or the isolation of Basidiobolus ranarum from such specimens or identification by molecular methods.
The PubMed and Scopus databases were searched for articles (in English, French, Spanish
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languages) published between 1964 and 2017 using the following combination of MESH terms: basidiobolomycosis AND gastrointestinal; basidiobolomycosis AND abdominal infection;
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Basidiobolus ranarum AND gastrointestinal infection; entomophtoromycosis AND gastrointestinal. Articles were reviewed in detail by 2 of us (M.D.P. and V.D.C.) to determine whether cases met the inclusion criteria. Additional cases were identified by reviewing references. Several cases were
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reported more than once and duplicates were excluded.
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ACCEPTED MANUSCRIPT 3. Results 3. 1 Case report In March 2013, a 25-year-old Italian male was admitted to a specialized oncological institute in Milan, for a suspect bowel neoplasm. He had a history of epigastric and lower right abdominal pain
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over the last two months so he had done on February an US abdomen which showed a mass in the right lumbar-hypogastric region of 65 mm in transverse diameter with associated retroperitoneal lymph nodes. The patient was an otherwise healthy man with an unremarkable past medical history;
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he was living in Cork, Ireland, working as a cook in a hotel.
Physical examination showed no abnormalities except a palpable tender mass on the right lower
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quadrant; on laboratory investigations white blood cell count was 10.1 x 109/L (normal value 4.411.3) with 0.99 x 109/L eosinophils (normal value 0.04-0.4), hemoglobin level of 15.6 g/dL, normal liver function tests, electrolyte levels and creatinine levels. CT scan of the pelvis and lower abdomen showed diffuse circumferential wall thickening affecting distal ileal loop and cecum,
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narrowing of lumen and regional lymph node involvement (Figure 1a). Colonoscopy was performed, revealing a complete stricture of the ascending colon due to an ulcerated mass (Figure 1b). Biopsies were taken and histopathology showed granulomatous and necrotizing inflammation.
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Because of a clinical profile suggestive of malignancy with colonic obstruction a right hemicolectomy was done. At the histology examination there were areas of necrotizing
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inflammation with marked eosinophilic infiltrate and foreign body- type giant cell reaction; fungal hyphae were seen within some of the multinucleated giant cells and a presumptive diagnosis of intestinal zygomycosis was done by the pathologist. The patient was referred to our Infectious diseases ward for further evaluation and management. Upon reviewing the pathology material, the hyphae had few septa, were highlighted by the PAS and Grocott stains and surrounded by eosinophilic and hyaline material (Splendore-Höeppli phenomenon) (Figure 2). The identification of the fungus was established by DNA extraction from formalin-fixed paraffin embedded tissue and panfungal polymerase chain reaction (PCR) 5
ACCEPTED MANUSCRIPT amplification of 18S rRNA. Amplified fragment had 99% identity with Basidiobolus ranarum (13) (Figure 3). Because preoperative diagnosis was presumed to be malignant, no tissue was sent for culture. Pending molecular typing of fungus, the patient was started on liposomal amphotericin B at
and clinical failure with amphotericin B has been described.
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the dose of 5 mg/kg, 4 days later substituted with itraconazole po 200 mg BID because resistance
Immunological deficiencies were excluded by additional investigations (lymphocyte
subpopulations, HIV, HBV, HCV, immunoglobulins, C3 and C4, oxidative BURST, T-lymphocyte
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maturation study and CD11b expression on neutrophils and monocytes). Complete blood count, apart from eosinophilia (12% maximum), was normal as other laboratory results. US abdomen
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before discharge showed hepatosplenomegaly, normal ileal and colic loops without any mass. The patient was discharged in April with oral itraconazole 200 mg BID and regular follow-up was started.
After 3 months abdominal CT was negative. In January 2014 the patient repeated US abdomen,
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showing only splenomegaly, and laboratory tests (white blood cell count 7.4 x 109/L with 0.23 x 109/L eosinophils). He received itraconazole 200 mg x 2/daily for a total of 9 months; at one year
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follow up he is in good health without relapse of the disease.
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3. 2 Review of the literature Gastrointestinal basidiobolomycosis (GIB) has been considered an extremely rare disease with only six cases reported in the literature up to 1994 [4,12,14-16].However, starting from 1995 a cluster of
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cases of GIB was described from Arizona with 19 patients (89 % resident in Arizona) identified between 1995 and 2009 at Mayo Clinic, Scottsdale (Arizona) [17-20 ].Eight of these 19 patients had been described separately before being finally reviewed by Vikram et al. in 2012 together with
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other 25 cases observed outside the United States [21]. All the detailed published cases (with the exception of 12 cases reported in the review by Vikram and not singularly described) plus the one
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observed by us are summarised in table 2 [4,12,14-20, 22-62]. We noted that a further 18 pediatric cases of basidiobolomycosis were reported in 2017 but they are not included in the present review because of the lack of any detailed information regarding single cases [63]. Eleven cases were reported in a 36-year period (1964-2000; a mean of 0.3 cases/year) and 78 in the last seventeen
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years (2001-2017; a mean of 4.6 cases/year) with a 15.3-fold increase. Overall, we considered for the purpose of our review the forty-four cases previously reviewed by Vikram et al. in 2012 plus fifty-eight new cases (including our present observation) described in detail after 2008 [21] (Table
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3). A male prevalence was observed (76/102, 74.5%) with a 3:1 ratio. All but one patient were immunocompetent [59]. The median age was 19 years (range 1-81 years) and 42 patients (41.2%)
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were children (age 1-13 years). The countries of residence in 79.4% of patients were only three: Saudi Arabia (37.2%), USA (21.6%) and Iran (20.6%) (Figure 4). Abdominal pain (86.3%) was the most common presenting symptom followed by weight loss (33.3%), abdominal distension (16.7%), vomiting (15.7%) and diarrhea (13.7%) (Table 3). Fever was reported only in 40.2% of patients and an abdominal mass was palpable in 30.4% of cases. Peripheral blood eosinophilia was detected in 85% of patients for whom this data was available. An initial misdiagnosis was made in 68 % of cases (68/102) with neoplasms and inflammatory bowel disease being the more frequently considered diagnosis (55.8%).In 32 cases (31.4%) the diagnosis was obtained by histopathology 7
ACCEPTED MANUSCRIPT plus culture and/or polymerase chain reaction (PCR), in 66 patients (64.7%) only by histopathology . In four cases the correct diagnosis was achieved only post-mortem. Overall, culture for B. ranarum was positive in 34/53 cases (64.2%). Identification by PCR was obtained in 5 cases. Colon-rectum were involved in 84.2% of cases. On histopathology the presence of fungal hyphae, granulomatous
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inflammation, eosinophilic infiltration together with the Splendore-Höeppli phenomenon observed in the gastrointestinal tract should be considered highly suggestive for B. ranarum. Overall 93/102 (91.2%) patients received an antifungal therapy Surgery plus antifungal treatment was employed in
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(36.4%). Overall death was observed in 18.6% of patients.
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79/102 (77.5%) of patients . Eleven patients received only antifungal treatment of which four died
4. Discussion
Basidiobolus ranarum is an environmental filamentous fungus that belongs to the phylum Entomophthoromycota , class Basidiobolomycetes formerly designated as zygomycetes. Recent
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phylogenetic studies showed that Entomophthromycota is a monophyletic lineage characterized by coenocytic vegetative cells, sporulation by production of infective conidia and production of zygospores capable of survival under unfavourable environmental conditions. Basidiobolus spp.
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form uninucleate cells with extremely large nuclei and had an haploid genome that has been estimated to be 10 times larger (350 Mb) than that of the average size of fungi [64]. The fungus
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grows at 30°C in 2-3 days with yellow-gray flat colonies but after 7-10 days colony become overgrown with mycelia as masses of zygospores. After its initial description by Eidam in 1886 [1], Basidiobolus ranarum was subsequently cultured from intestinal contents of frogs [65] and several other species of amphibians and reptiles, from decaying plant material, from an insectivorous bat (Rhinopoma hardwickei hardwickei) in India and from the faeces of kangaroos in Australia. The disease initially associated with B. ranarum was described in Indonesia in 1956 by Joe et al. [9] as subcutaneous phycomycosis and subsequently the same presentation was identified in other areas of tropical and subtropical climate, especially from 8
ACCEPTED MANUSCRIPT Uganda, Nigeria and Indonesia. In 1964 the first case of gastrointestinal involvement was described in a 6-year old Nigerian boy at postmortem examination [4]. Gastrointestinal basidiobolomycosis (GIB) has been considered an extremely rare disease with only six cases reported up to 1999 [63].. Within the past 2 decades a 15-fold increase in cases of gastrointestinal infection by B. ranarum has
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been reported worldwide. Although most of the cases have been described in the Middle East (Saudi Arabia, Iran, Iraq, Kuwait, Oman, Qatar) [23-26,29,31-39,41-46,48-50,52-55,57,60,62] and the southwestern of United States (Arizona and Utah) [15,17-20,40,47,56], sporadic reports came
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from South America, Africa , Europe and the Indian Subcontinent [4,12,14,16,27,28,30,51, 59,PR] and no clear environmental risk factors have been identified. In the case-control study performed by
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Lyon et al. in Arizona, ranitidine use (OR 6.0) and a longer period of smoking (OR 2.1/additional 20 years of smoking) were both associated with the development of the disease [20]. It has been hypothesized that the decreased gastric acidity together with the alteration of white blood cells activity induced by smoking might contribute to the survival of ingested B. ranarum. However,
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rural environment and activities such as gardening and landscaping as well as ingestion of contaminated soil or fruits and vegetables seem to be associated with a higher risk of exposure to the infection [21]. Since B. ranarum usually involves immunocompetent subjects, factors
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associated with health history of the hosts are not helpful for the diagnosis that is therefore frequently delayed. Of the three patients reported in Europe [27,30, PR], only the one described
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here was diagnosed during life. However, at least in endemic areas, a higher awareness of GIB by clinicians might partially account for the increase in the number of cases reported in the last decades. As in previous cases, in our patient the route of acquisition of the disease remains unknown; however since B. ranarum can be found in soil and decaying vegetables, we hypothesized that the consumption of homebrew unpasteurized and unfiltered beer might have been the source of fungal ingestion and subsequent involvement of the intestine. A preliminary misdiagnosis among patients with GIB was commonly reported in the literature, the most frequent being gastrointestinal malignancy and inflammatory bowel diseases 9
ACCEPTED MANUSCRIPT [17,22,30,33,34,36,37,41,42,56,61,62, PR], although a suspicion should be raised whenever fever and abdominal pain occur in young patients with gastrointestinal, abdominal mass or intestinal wall thickening in association with high eosinophilia. Although a definite diagnosis can be obtained with culture [14,15,18,19,22-
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24,30,33,35,41,45,47,49-51,54,59,62], it was frequently missed in previous reports because of the lack of suspicion that made tissue specimens unavailable for culture purpose. Therefore, the diagnosis of gastrointestinal infection by B. ranarum was mainly obtained on histologic
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examination, which typical morphologic features include granulomatous inflammation and a diffuse eosinophilic infiltrate with thin walled branched hyphae surrounded by eosinophilic material
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(Splendore-Höeppli phenomenon) and sometimes zygospores (spherical bodies with foamy cytoplasm) [4,6,12,16,17,20,24,26-29,31-33,35-39,42-44,46,49,52,53,55,58,60,61]. The immunodiagnostic test such as immunodiffusion is not standardized yet, since it showed a high specificity but a controversial sensitivity [20]. Finally, since suitable specimens for culture purpose
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are often unavailable, molecular diagnosis from formalin fixed paraffin embedded tissue represents the optimal adjunctive diagnostic method to histology, as it showed a high specificity and high sensitivity [34,40,51,54,PR].
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Treatment of GIB usually requires a combination of surgical and medical approach. Surgical resection of infected bowel tissues must be followed by itraconazole for at least 6 months to prevent
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recurrence. There are also a few cases described in the literature that showed a successful outcome with antifungal treatment alone [33-35, 42,56,61]. The role of amphotericin B has been overcome since resistance has been observed in more than 50% of cases [25]. Potassium iodide (KI) has been traditionally used for the treatment of subcutaneous basidiobolomycosis and more recently it was employed successfully in a single case report of a child with GIB [21,66,67]. However, as suggested by Bering et al., the absence of demonstrable in vitro activity of KI against B. ranarum coupled with several possible limitations (toxicity associated with high doses, lack of any standard prescription recommendation, available new azoles) do not recommend its use in GIB [68]. More 10
ACCEPTED MANUSCRIPT recently successful treatments with voriconazole [42,49,50,53-55,58,59] and posaconazole [40,48,50] have been reported. On the basis of the experience reported in the literature azoles should be considered the drugs of choice for GIB. 5. Conclusions
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In conclusion, GIB should be suspected in patients complaining abdominal pain associated with gastrointestinal and/or colon mass who has concomitant peripheral eosinophilia especially if they come from the Middle-East or arid zone from USA. Moreover, the observation of the Splendore-
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Höeppli phenomenon (although not pathognomonic being associated with several microorganisms) [69] in the presence of zygomicetes in tissue samples from immunocompetent patients should raise
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the suspicion of basidiobolomycosis and confirmation by using molecular diagnosis should be sought through pathologists able to do it. Although some reports indicate successful outcome by using only medical therapy, surgery with resection of affected bowel segments associated with prolonged antifungal treatment should be advised. Itraconazole seems to be the best available
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treatment although other new azoles have also been successfully employed. The exact length of
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duration of antifungal therapy remains to be established.
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ACCEPTED MANUSCRIPT [44] Hassan HA, Majid RA, Rashid NG, Nuradeen BE, Abdulkarim QH, Hawramy TA, et al. Eosinophilic granulomatous gastrointestinal and hepatic abscess attributable to basidiobolomycosis and fascioliasis. A simultaneous emergence in Iraqui Kurdistan. BMC Infect Dis 2013;13:91.
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[45] Alshehri AH, Alshehri A, Bawahab MA, Al-Humayed S, Nabrawi K, Alamri FS, et al. Basidiobolomycosis: an emerging fungal infection of the gastrointestinal tract in adults. Am J Infect Dis 2013;9:1-6.
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[46] Al-Qahtani SM, Alsuheel AM, Shati AA, Mirza NI, Al-Qahtani AA, Al-Hanshani AA, et al. Case reports: gastrointestinal basidiobolomycosis in children. Curr Pediatr Res 2013;7:1-6.
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[47] Pandit V, Rhee P, Aziz H, Jehangir Q, Friese R, Joseph B. Perforated appendicitis with gastrointestinal basidiobolomycosis: a rare finding. Surg Infect 2014, 15:339-42. [48] Zabolinejad N, Naseri A, Davoudi Y, Joudi M, Aelami MH. Colonic basidiobolomycosis in a child: report of a culture – proven case. Int J Infect Dis. 2014 ;22:41-3
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[49] Alahmadi R, Sayadi H, Badreddine H, Linijawi A, Baatrup G, Al-Maghrabi J. Gastrointestinal basidiobolomycosis, the experience of a tertiary care hospital in the western region of Saudi Arabia and report of four new cases. Life Sci J 2014;11:344-352.
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[50] Al-Maani AS, Paul G, Jardani A, Nayar M, Al-Lawati F, Al-Baluishi S, Hussain IB. Gastrointestinal basidiobolomycosis. First case report from Oman and literature review. Sultan
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Qaboos University Med J 2014;14:e241-44. [51] Cazorla A, Grenouillet F, Piton G, Faure E, Delabrousse E, Mathieu P, et al. Une forme gastro-intestinale de basidiobolomycose d’evolution fatale. Ann Pathol 2014;34:228-32. [52] Ejtehadi F, Anushiravani A, Bananzadeh A, Geramizadeh B. Gastrointestinal basidiobolomycosis accompanied by liver involvement: a case report. Iran Red Crescent Med J 2014;16:e14109.
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ACCEPTED MANUSCRIPT [53] Albaradi BA, Babiker AM, Al-Qahtani HS. Successful treatment of gastrointestinal basidiobolomycosis with voriconazole without surgical intervention. J Trop Pediatr 2014; 60:476-9. [54] Alhuraiji A, Alqaraawi A, Alaraj A, Al-Abdely HM, Alrajhi AA. Chronic abdominal pain
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and intestinal obstruction in a 24-year-old woman. Clin Infect Dis 2014;58:990;1035.
[55] Al-Naemi AQ, Ali Khan L, Al-Naemi I, Amin K, Ali Athlawy Y, Awad A, et al. A case
Medicine 2015;94:e1430.
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report of gastrointestinal basidiobolomycosis treated with voriconazole. A rare emerging entity.
[56] Ilyas MI, Jordan SA, Nfonsam V. Fungal inflammatory masses masquerading as colorectal
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cancer: a cse report. BMC Res Notes 2015;8:32.
[57] Geramizadeh B, Sanai Dashti A, Kadivar MR, Kord S. Isolated hepatic basidiobolomycosis in a 2-year old girl: the first case report. Hepat Mon 2015;15:e30117. [58] Mandhan P, Hassan KO, Samaan SM, Ali MJ. Visceral basidiobolomycosis: an
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overlooked infection in immunocompetent children. Afr J Paediatr Surg 2015;12:193-6. [59] Sethi P, Balakrishnan D, Surendran S, Umer Mohamed Z. Fulminant zygomycosis of graft
2015-214097.
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liver following liver transplantation. BMJ Case Rep 2016; pii: bcr2015214097. doi:10.1136/bcr-
[60] Ageel HI, Arishi HM, Kamli AA, Hussein AM, Bhavanarushi S. Unusual presentation of
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Gastrointestinal Basidiobolomycosis in a 7-year-old Child – Case Report. Am J Med Case Rep 2017;5:131-4.
[61] Almoosa Z, Alsuhaibani M, Aidandan S, Alshahrani D. Pediatric gastrointestinal basidiobolomycosis mimicking malignancy. Med Mycol Case Rep 2017,18:31-33. [62] Zekavat OR, Abdalkarimi B, Pouladfar G, Fathpour G, Mokhtari M, Shakibazad N. Colonic basidiobolomycosis with liver involvement masquerading as gastrointestinal lymphoma: a case report and literature review. Rev Soc Bras Med Trop 2017;50:712-4.
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ACCEPTED MANUSCRIPT [63] Shreef K, Saleem M, Saeedd MA, Eissa M. Gastrointestinal Basidiobolomycosis: An Emerging, and A Confusing, Disease in Children (A Multicenter Experience). Eur J Pediatr Surg 2018;28:194-9. [64] Henk DA, Fisher MC. The gut fungus Basidiobolus ranarum has a large genome and
2012;7(2):e31268.
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different copy numbers of putatively functionally redundant elongation factor genes. PLoS One.
[65] Sutherland-Campbell H. An attempt to prove the etiologic factor in an epidemic among
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orange workers. Arch Dermatol Syphilol 1929; 19:233–254.
[66] Sanaei Dashti A, Nasimfar A, Khorami HH, Pouladfar G, Kadivar MR, Geramizadeh B, et
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al. Gastro-intestinal basidiobolomycosis in a 2-year-old boy: dramatic response to potassium iodide. Paediatr Int Child Health 2018, 38:150-3.
[67] Vilela R, Mendoza L. Human pathogenic Entomophthorales. Clin Microbiol Rev 2018;31:e00014-18.
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[68] Bering J, Mafi N, Vikram HR. Basidiobolomycosis: an unusual, mysterious, and emerging endemic fungal infection. Paediatr Int Child Health 2018;38:81-4.
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[69] Gopinath D. Splendore-Höeppli phenomenon. I Oral Maxillofac Pathol 2018;22:161-2.
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ACCEPTED MANUSCRIPT Figure legends Figure 1. Computed tomography scan showing a mass in the ascending colon Figure 2. (A,B) Histopathologic section of colon showing granumomatous inflammation of the colonic wall with prominent eosinophilic infiltrate with a transversely cut hypha (black arrow)
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surrounded by an intensely eosinophilic cuff (Splendore-Hoeppli phenomenon, white arrow) (Hematoxylin-eosin x100 and x400). (C,D) Detailed view of large fungal hypha surrounded by eosinophilic Splendore-Hoeppli material and numerous eosinophils and polymorphonuclear
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leucocytes (E&E x 400).
Figure 3. Panfungal PCR that amplifies the internal transcriber space (ITS) region of the rDNA
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gene performed on multiple samples (F,B1,C3,A2) of paraffin-embedded tissue specimens from different areas of the mass. Sequenced amplicons gave a 99% matching with Basidiobolus ranarum (One µg and 100 nanograms, respectively were tested).
Figure 4. Geographical distribution of cases of 101 gastrointestinal basidiobolomycosis reported
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worldwide (for one case the country was unknown).
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Table 1- Taxonomic classification of Basidiobolus ranarum within Entomophthoromycota phylum Previous Zygomycota
Actual Entomophthoromycota
Class
Zygomycetes
Basidiobolomycetes
Order
Entomophthorales
Basidiobolales
Family
Basidiobolaceae
Basidiobolaceae
Species
Basidiobolus
B. ranarum; B. haptosporus; B. heterosporus; B. magnus; B. meristoporus; B. microsporus ( plus undescribed new genera)
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Taxonomy Phylum
1
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Table 2. Chronological summary of 89 case reports of gastrointestinal basidiobolomycosis Age/sex
Clinical presentation
Leukocyte/Eosinophils/ Splendore-Hoeppli phenomenon NR/NR/NR
Organ involvement
Diagnosis
Therapy
Outcome
Nigeria
6/M
2/12
1977/1979
Brazil
13/M
3/12
NR/1979
Brazil
60/M
Subcutaneous lesions (penis, scrotum, perineum); bloody diarrhea Abdominal pain, fever, weakness, anorexia Abdominal pain
I; C; R; bladder
Post-mortem (histopathology)
Colostomy; antibiotics
Death
NR/16%/Yes
S; D; L; P; C; BT S; C
Post-mortem (histopathology) Histopathology; culture negative
Laparatomy
Death 11 days after surgery Cured
4/14
1979/1980
Brazil
4/M
Fever, abdominal pain, sweats, diarrhea
13,500 µL/26%/Yes
S; C
19,500 µL/6%/Yes
I; Ce; C
Histopathology; culture (Basidiobolus haptosporus) Histopathology/culture (B.haptosporus/ranarum)
12,600 µL/11%/Yes
I; Ce; C:
Histopathology
Surgery/
Death 12 days after surgery (peritonitis) Death 4 weeks after laparotomy NR
5/15
NR/1986
USA
69/M
6/16
1989/1997
Brazil
19/M
7/17
1994/1997
USA
49/F
8/22
1996/1998
Kuwait (Bangladesh)
30/M
Fever, abdominal pain, nausea, constipation, vomiting, right lower quadrant mass Fever, abdominal mass, weight loss, sweats Abdominal and rectal pain, constipation followed by mucus and bloody diarrhea Rectal bleeding, constipation, rectal mass
23,400 µL/NR)/Yes
C; R
Histopathology/serology
Surgery/Itracona zole (5 months)
Alive after 13 months
18-22,000 µL/NR/NR
R
Histopathology/Culture (B.ranarum)/serology
Lost to followup
26,400 µL/10%/NR
S; P
Histopathology
12,100 µL/6%/NR
C
16,400 µL/8%/ Yes
S ; C ; R; ureter
Histopathology/Culture (B.ranarum) Histopathology/Culture (B.ranarum)
Abdominal pain, abdominal mass
NR/NR/Yes
I ; Ce ; appendix ; retroperitone um
Histopathology/Culture (B.ranarum)
Surgery/AmB (3weeks)+ketoco nazole (1 week) Surgery/Itracona zole (9.5 months) Surgery/Itracona zole Surgery/AmB (1week)+ itraconazole (11 months) ; terbinafine 2 months Surgery/Itracona zole (19 months)
9/18
1998/1999
USA
37/F
Abdominal pain
10/ 18
1998/1999
USA
59/M
11/19
1997/1999
USA
57/M
Abdominal pain, mucus, colonic obstruction Abdominal pain, anorexia, fatigue, constipation
12/20
1996/2001
USA
46/M
13/20
1998/2001
USA
52/M
Abdominal pain
12,800 µL/14,3%/Yes
C
Histopathology/ culture negative/serology
Surgery/Itracona zole (10 months)
14/20
1999/2001
USA
59/M
Abdominal pain, constipation
NR/NR/NR
Ce; C
41/M
Fever, abdominal pain,
NR/NR/Yes
Ce; C
Histopathology/Culture not done Histopathology/Culture
Surgery/Itracona zole (10 months) Surgery/LAmB
15/23
1999/2001
Kuwait
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Country
1/4
Year observation/ Publication NR/1964
TE D
M AN U
SC
NR/NR/Yes
AC C
EP
Patient/Reference
Gastrectomy & hemicolectomy; AmB Surgery
Surgery/AmB
Cured
Cured Cured
Alive (31 months ; 12 months after itraconazole withdrawal) Alive 4 months after itraconazole withdrawal) Alive Lost to follow-
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I; Ce; C; L; BT
11,000 µL/20%/Yes
I; Ce; C
Histopathology
18/ 24
2001/2003
Saudi Arabia
9/M
Fever, abdominal pain
17,800 µL/19.8%/NR
19/ 24
2002/2003
Saudi Arabia
4/M
Fever, abdominal pain, hepatomegaly
30,000 µL/30%/NR
20/ 24
2001/2003
Saudi Arabia
3/M
Fever, abdominal pain, heaptomegaly, ascites
24,500µL/18%/Yes
21/ 24
2000/2003
Saudi Arabia
7/M
16,900 µL/17%/Yes
22/25
NR/2003
Saudi Arabia
12/M
17,900 µL/20%/Yes
I; Ce; C
Histopathology/Culture (B.ranarum)
Surgery/Itracona zole (10 months)
Alive
23/26
NR/2004
Iran
45/M
Fever, abdominal pain, abdominal distension, hepatosplenomegaly Fever, abdominal pain, anorexia, weight loss, vomiting, constipation Abdominal pain
NR/NR/Yes
Ce; L
Histopathology
Alive
24/27
NR/2004
Italy
40/F
Fever, subcutaneous lesions
28,320 µL/30%/Yes
Post-mortem (histopathology)
25/28
1990/2005
Brazil
43/M
10,800 µL/NR/Yes
Histopathology
26/29
NR/2006
Iran
1.5/M
Fever, abdominal pain, vomiting, weight loss Fever, abdominal pain, diarrhea, hematochezia
L; P; S; M; lung; spleen; kidneys; uterus P
Surgery/Ketocon azole+cotrimoxa zole (4 weeks) -
NR/Yes/Yes
R
Histopathology
27/30
NR/2006
The Netherlands
61/M
NR/27.7%/Yes
C; L; gallbladder
Histopathology; culture post-mortem B.ranarum
28/31
NR/2007
Saudi Arabia
13/M
Abdominal pain, tenderness
NR/NR/Yes
C
29/32
Iran
18/M
Abdominal pain, constipation
12,000 µL/8%/Yes
I
Iran
2.5/M
C
Histopathology
Iran
2/M
29,400 µL/ 16%/Yes
C
Histopathology
32 /33
2000/2009
Saudi Arabia
77/M
Abdominal pain, constipation, rectal bleeding Abdominal pain, distension, ascites Abdominal pain, abdominal mass, weight loss, rectal bleeding
26,800 µL/10%/Yes
31 / 32
20022007/2007 20022007/2007 2002/2007
Histopathology/Culture negative Histopathology
Normal/NR/Yes
Ce; C
Histopathology
30 / 32
SC
Saudi Arabia
M AN U
2001/2003
TE D
17/ 24
12/M
Abdominal pain, constipation
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16,000 µL/15%/Yes
12/M
Fever, abdominal pain, abdominal mass, scrotal swelling Fever, abdominal pain
from urine (B.ranarum)/serology Histopathology/Culture (B.ranarum)
EP
2000/2003
abdominal mass
AC C
16/24
(Indian patient) Saudi Arabia
Ce; C; R
L; intestine
L
R; D; BT
Histopathology/Culture (B.ranarum) Histopathology/Culture (B.ranarum) from liver biopsy Histopathology/Culture (B.ranarum) from liver biopsy Histopathology (liver biopsy)
(4 weeks)
up
Surgery/Itracona zole (> 24 months) Surgery/AmB than itraconazole (12 months) Surgery/Itracona zole (10 months) AmB than itraconazole (> 12 months) AmB+5Flu
Alive
AmB+itraconazo le (12 months)
Surgery/ketocon azole (35 days) Surgery/AmB (1 week) than itraconazole (9 months) Cholangiodrain/ AmB
Surgery/Itracona zole Surgery/Itracona zole Surgery/Itracona zole Surgery/Itracona zole Surgery/Itracona zole (2 weeks)
Alive
Alive Alive
Death of MOF 2 days after admission Death (massive GI bleeding)
Death due shock and pulmonary failure Follow-up not stated Alive
Death due to MOF few days after start antifungal therapy Alive Alive (7 years) Alive (10 years) Alive (7 years) Lost to followup
3
33/33
2001/2009
Saudi Arabia
19/F
Fever, abdominal pain, weight loss
NR/NR/Yes
Ce; C
Histopathology/ Culture (B. ranarum)
34 /33
NR/2009
Saudi Arabia
20/M
NR/NR/Yes
C
35/34
NR/2011
Saudi Arabia
10/M
Abdominal mass, weight loss, ematochezia Fever, abdominal pain, vomiting
12,200 µL/17%/Yes
Ce;
36/35
2003/2011
Saudi Arabia
6/M
32,700 µL/11%/NR
37/ 35
2003/2011
Saudi Arabia
13/F
Fever, abdominal pain, abdominal mass Fever, abdominal pain
I; Ce; C
Histopathology/ Culture (B. ranarum) Histopathology/ PCR (B.ranarum) Histopathology/ Culture (B.ranarum) Histopathology
38/ 35
2003/2011
Saudi Arabia
8/F
Fever, anorexia, abdominal distension, weight loss
13,800 µL/4%/Yes
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P; L; BT
Histopathology
39/36
NR/2011
Saudi Arabia
25/F
12,800 µL/NR/Yes
C
Histopathology
40 /37
2010/2012
Saudi Arabia
2/M
14,000 µL/19%/Yes
I; Ce; C
Histopathology
41/38
NR/2012
Iran
12/M
Abdominal pain, weight loss, nausea, rectal bleeding Fever, abdominal pain, abdominal mass, vomiting , diarrhea Fever, abdominal pain, vomiting, bloody diarrhea
28,100 µL/16%/Yes
C
Histopathology
42/39
20082012/2012
Iran
1.3/F
Abdominal pain, distension
23,000 µL/17%/Yes
S; C; M
Histopathology/Culture negative
Itraconazole (12 months) AmB than itraconazole Surgery/AmB+it raconazole (12 months) Surgery/AmB than itraconazole (18 months) Surgery/Itracona zole AmB than voriconazole (12 months) Surgery/AmB (1 week) than posaconazole Surgery/AmB than itraconazole
43/ 39
20082012/2012 20082012/2012 20082012/2012 20082012/2012 20082012/2012
Iran
5/M
Abdominal pain, weight loss
21,300 µL/20%/Yes
C
Iran
5/M
Abdominal pain
16,100 µL/10%/Yes
C
Iran
2/M
Abdominal pain, diarrhea
17,400 µL/20%/Yes
I; C
Iran
16/M
Abdominal pain
11,500 µL/14%/Yes
C
Iran
1.3/M
Abdominal pain, diarrhea
18,200 µL/8%/Yes
S; I; C; M
Histopathology/Culture negative Histopathology/Culture negative Histopathology/Culture negative Histopathology/Culture negative Histopathology/Culture negative
Surgery/AmB than itraconazole Surgery/AmB than itraconazole Surgery/AmB than itraconazole Surgery/AmB than itraconazole Surgery/AmB than itraconazole
20082012/2012 20082012/2012 20082012/2012 20082012/2012 20082012/2012 NR/2013
Iran
1.1/M
Abdominal pain, bloody stool
23,000 µL/16%/Yes
C
Iran
37/M
Abdominal pain
20,000 µL/10%/Yes
C
Iran
28/M
Abdominal pain
14,000 µL/10%/Yes
C
Iran
52/M
17,000 µL/15%/Yes
C
Iran
42/F
Abdominal pain, vomiting, diarrhea Abdominal pain
17,000 µL/15.9%/Yes
I; C
USA
67/M
Abdominal pain
NR/NR/Yes
I
Histopathology/Culture negative Histopathology/Culture negative Histopathology/Culture negative Histopathology/Culture negative Histopathology/Culture (B.ranarum) Histopathology/ PCR (B.ranarum)
Surgery/AmB than itraconazole Surgery/Itracona zole Surgery/Itracona zole Surgery/Itracona zole Surgery/Itracona zole Surgery/Ureteral stent/Fluconazol
47/ 39
48 / 39 49/ 39 50 / 39 51 / 39 52 / 39 53 /40
SC
M AN U
TE D
46 / 39
EP
45 / 39
AC C
44 / 39
14,500 µL/18%/Yes
Ce; C; L
LAmB+itracona zole; ketoconazole (4 years) Voriconazole
Alive (4 years)
Alive Alive (1 year) Alive (2 years) Alive (2 years)
Alive 2,5 years) Alive Alive (1 year)
Follow-up not stated Death due to disseminated disease Alive (8 months) Alive (3 years) Alive (6 months) Alive (2 years) Death due to disseminated disease (1,5 months) Alive (1 year) Alive (6 months) Alive (2 years) Alive (6 months) Alive (1year) Alive (2 years)
4
ACCEPTED MANUSCRIPT
NR/2013
Saudi Arabia
4/M
Fever, abdominal pain, vomiting, weight loss
17,000 µL/13.6%/Yes
55 /42
NR/2013
Saudi Arabia
5/M
15,600 µL/15%/Yes
56 /43
NR/2013
Iran
12/M
Fever, abdominal pain, bloody diarrhea, anorexia, weight loss Fever, abdominal pain , hematuria
57/44
2010/2013
Iraq
48/M
58 /44
2010/2013
Iraq
1.5/M
59 / 44
2010/2013
Iraq
59/M
60 / 44
2012/2013
Iraq
53/M
61/ 44
2012/2013
Iraq
39/M
62 / 44
2012/2013
Iraq
1.5/M
63 /45
NR/2013
Saudi Arabia
24/M
64 / 45
NR/2013
Saudi Arabia
21/F
65 / 45
NR/2013
Saudi Arabia
72/M
66 / 45
NR/2013
Saudi Arabia
19/M
67 /46
20092012/2013 20092012/2013
Saudi Arabia
12/F
Saudi Arabia
1.5/M
Saudi Arabia
9/F
70/47
20092012/2013 NR/2013
USA
34/F
71/48
NR/2013
Iran
3/M
69/ 46
Ce; C; L
Histopathology
NR
Histopathology
NR/No/Yes
Ce
Histopathology
NR/NT/Yes
Ce; C
Histopathology
NR/9%/Yes
O; C
Histopathology
NR/21%/Yes
Ce; C
Histopathology
14,400 µL/22%/NR
I; Ce; C
Histopathology/ Culture (B.ranarum) Histopahology/Culture (B.ranarum)
Surgery/Itracona zole (6 months) Surgery/Itracona zole (6 months) Surgery/Itracona zole (7 months) Surgery/Itracona zole (4 months) Surgery/Itracona zole (12 months) Steroid/Itraconaz ole
SC
M AN U
NR/29%/Yes
EP
TE D
Fever, abdominal pain, weight loss, abdominal mass Fever, abdominal pain, weight loss, Fever, weight loss, cough, sore throat Fever, abdominal pain, abdominal mass, weight loss Fever, abdominal pain, weight loss, diarrhea Fever, abdominal pain, diarrhea alternate with constipation, weight loss Fever, abdominal mass
Fever, abdominal pain, abdominal mass
AC C
68 / 46
I; C
NR/12%/Yes
Fever, abdominal pain, constipation Fever, hepatomegaly
Abdominal pain, constipation, vomiting Abdominal pain, constipation, vomiting, weight loss Abdominal pain, abdominal mass
C
Histopathology/ Culture (B.ranarum) Histopathology/Culture negative Histopathology
14,500 µL/No/Yes
Fever, abdominal pain, weight loss Fever, abdominal pain, weight loss, abdominal mass
I; Ce; C
RI PT
54 /41
e (several months); posaconazole 600 (1 year) Surgery/Voricon azole (12 months) Voriconazole (6 months) Surgery/Itracona zole + AmB (2 weeks) then itraconazole Surgery/Itracona zole (6 months) AmB
7,100 µL/No/NR
Ce; C; R
15,280 µL/No/NR
Ce; C
Histopahology/Culture (B.ranarum)
Surgery/Itracona zole
22,100 µL/6.65%/NR
Ce; C
Histopahology/Culture (B.ranarum)
Surgery/Itracona zole
17,600µL/35%/Yes
I; Ce
Histopathology
24,520 µL/10.2%/Yes
L
Histopathology
Surgery/Itracona zole Surgery/Itracona zole
17,800 µL/14%/Yes
C
Histopathology
13,000 µL/16.9%/NR
I; Ce
Histopahology/Culture (B.ranarum)
12,500 µL/6%/Yes
C
Histopahology/Culture (B.ranarum)
Surgery/Itracona zole (8 months) Surgery/Itracona zole+ LAmB (6 weeks) Surgery/Posacon azole (3 months)
Alive (1 year)
Alive (6 months) Death for septic shock
Alive (1 year) Death for intestinal perforation Alive (> 1 year) Alive (10 months) Alive (7 months) Alive (4 months) Alive (1 year) Death for HCassociated infection Death for bowel perforation and ARDS, septic shock (32 days post-surgery) Death for HCassociated infection Alive Death for ARDS after few days Alive (8 months) Alive
Alive (15 months)
5
ACCEPTED MANUSCRIPT
2001/2014
Saudi Arabia
43/M
Abdominal pain, weight loss
15,000 µL/27%/Yes
Ce; C; L
73 / 49
2005/2014
Saudi Arabia
20/F
NR/NR/NR
C
74 / 49
2008/2014
Saudi Arabia
63/M
Abdominal pain, abdominal mass Abdominal pain, weight loss
12,400 µL/14%/Yes
I; C
75 / 49
2011/2014
Saudi Arabia
20/F
Rectal bleeding
14,000 µL/20%/Yes
76 /50
2012/2014
Oman
5/F
Abdominal pain, nausea, vomiting, low grade fever
14,200 µL/50%/Yes
77/51
2014
Mali/France
55/M
Abdominal pain
NR/NR/Yes
78/52
2012/2014
Iran
41/F
79/53
2014
Saudi Arabia
11/M
Abdominal pain, weight loss, nausea, fever Abdominal pain
80/54
2014
Saudi Arabia
24/F
81/55
2014/2015
Saudi Arabia
82/56
/2015
83 /57
2015
USA (Arizona) Iran
84/58
2015
85 /59
SC
RI PT
72/49
Histopahology/Culture /(B.ranarum) from liver Histopahology/Culture (B.ranarum) Histopathology/Culture negative
R
Histopathology
Ce, C
Histopathology/Culture positive (Basidiobolus spp.)
I;C I; Ce; L
NR/Yes/Yes
C
Histopathology
7,070 µL/14,6%/Yes
L; C; P
36/M
Abdominal pain, nausea, vomiting, abdominal distension, constipation Suspected appendicitis
16,000 µL/18%/Yes
Ce
Histopathology/Culture & PCR positive (B. ranarum) Histopathology
56/M
Abdominal pain, rectal pain
NR/NR/NR
Ce; R
Histopathology
2/F
Abdominal pain
11-12,000 µL/25-35%/Yes
L
Histopathology
Qatar
4/F
Abdominal pain, rectal bleeding, weight loss,
NR/NR/Yes
C
Histopathology
NR/2016
India
44/M
Liver transplant patient; rise in transaminases
NR/NR/NR
L
Culture (B. ranarum) of liver aspirate
86/60
NR/2017
Saudi Arabia
7/M
Abdominal pain, rectal bleeding, weight loss, fever
10,030 µL/15.9%/Yes
R
Histopathology
87/61
NR/2017
Saudi Arabia
7/F
19,000 µL(3000)/Yes
C;R
Histopathology
88/62
NR/2017
Iran
5/M
Abdominal pain, constipation, fever, palpable mass Abdominal pain, fever, anorexia, weight loss, vomiting
23,900 µL/11%/Yes
Ce; C; I
Histopathology/Culture (Basidiobolus spp.)
AC C
EP
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Histopathology /PCR (B. ranarum) Histopathology
then itraconazole (12 months) Surgery/Itracona zole (7 months) Surgery Surgery/Voricon azole (12 months) Drainage/Terbin afine+voriconaz ole (12 months) Surgery/LAmB+ posaconazole then voriconazole (4 months) Antituberculous treatment Surgery/Itracona zole (4 months) Voriconazole (12 months)
Voriconazole
Surgery/Itracona zole (4 months); voriconazole Itraconazole (12 months) Surgery/AmB (1 month) Surgery/Voricon azole (12 months) LAmB; itraconazole, caspofungin, posaconazole Surgery/Voricon azole (12 months) Voriconazole (9 months) Amphotericin B (2 months); posaconazole (6 months)
Alive (7 months) Death Alive (12 months) Alive (12 months) Alive (4 months)
Death (2 months) Alive (12 months) Alive (12 months after discontinuing therapy) Alive (2 months) Alive
Alive (12 months) Alive (9 months) Alive (12 months) Death (MOF and bacterial sepsis) Alive (12 months) Alive (10 months) Alive (6 months)
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89/ PR
2013/2018
Italy/Ireland
25/M
Abdominal pain
10,100 µL/10%/Yes
I; Ce; C
Histopathology/PCR (B.ranarum)
Surgery/Itracona zole (8 months)
Alive (13 months)
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Twelve patients reported with no details in the review by Vikram et al. are not described in the table. D, duodenum; E, esophagus; S, stomach; I, ileum; Ce, cecum; C, colon; R, rectum; O, oropharynx; BT, biliary tract; L, liver; P, peritoneum; M, mesentery; AmB, amphotericin B; LAmB, liposomal amphotericin B
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23 (22.5%) 17 (16.7%) 41 (40.2%) 34 (33.3%) 14 (13.7%) 16 (15.7%) 15 (14.7%)
1 (1.7%)
6 (5.9%)
43/47 (91.5%)
69/81 (85.2%)
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8/16 (50%)
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6 (10.3%) 3 (5.2%) 27 (46.5%) 22 (37.9%) 7 (12.1%) 10 (17.2%) 9 (15.5%)
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Constipation 17 (39%) Abdominal distension 14 (32%) Fever 14 (32%) Weight loss 12 (27%) Diarrhea 7 (16%) Vomiting 6 (14%) Lower gastrointestinal 6 (14%) bleeding Hepatomegaly 5 (11%) Laboratory test results* Peripheral blood 26/34 (76%) eosinophilia Positive Basidiobolus 8/16 (50%) serology
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Table 3. Clinical manifestations, laboratory studies , sites of involvement and preliminary diagnosis in 102 patients with gastrointestinal basidiobolomycosis Patients, proportion Total Patients, proportion Characteristic (%)- Present review (%) –Review by Vikram (1964-2008)21 (2009-2017) 44 (43.1%) 58 (56.9%) 102 Number of pts Age, years, median 37.3 (2-81) 17.5 (1.1-77) 19 (1.1-81) Male sex 36 (81.8%) 40 (68.9%) 76 (74.5%) Country of residence Brazil 4 (9%) 4 (3.9 %) Iran 4 (9%) 17 (29.3%) 21(20.6%) Iraq 6 (10.3%) 6 (5.9%) Saudi Arabia 11 (25%) 27 (46.5%) 38 (37.2%) USA 19 (43%) 3 (5.2 %) 22 (21.6%) Other 6 (13.6%) # 5 (8.6 %)§ 11 (10.8%) Signs and symptoms Abdominal pain 37 (84%) 51 (87.9%) 88 (86.3%) Abdominal mass 19 (43%) 31 (30.4%) 12 (20.7%)
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Growth of 17/24 (71%) 17/29 (58.6%) 34/53 (64.2%) Basidiobolus in culture 43/44 (98%) 57/57 (100%) 100/101 (99%) Characteristic histopathology Organ involvement Stomach 6 (14%) 2 (3.5%) 8 (7.9%) Small bowel 16 (36%) 16 (28.1%) 32 (31.7%) Colon/rectum 36 (82%) 50 (87.7%) 85 (84.2%) Liver/gallbladder 13 (30%) 10 (17.5%) 22 (21.8%) Pancreas 3 (5.3%) 3 (2.9%) Preliminary diagnosis Malignancy 19 (43%) 6 (10.9%) 25 (24.7%) Inflammatory bowel 7 (16%) 6 (10.9%) 13 (12.9%) disease Diverticulitis 5 (11%) 5 (4.9%) Appendicitis 3 (7%) 5 (9.1%) 8 (7.9%) Lymphoma 2 (5%) 4 (7.3%) 6 (5.9%) Gastrointestinal 2 (5%) 3 (5.5%) 5 (4.9%) tuberculosis Ameboma 1 (1.8%) 1 (0.9%) Schistosomiasis 1 (1.8%) 1 (0.9%) Other 4 (9%) 4 (3.9%) Antifungal treatment 37/43 (86%) 56/58 (96.5%) 93/101 (92.1%) Itraconazole 26/37 (70.3%) 24/56 (42.9%) 50/93 (53.8%) 2/56 (3.6%) 10/93 (10.7%) Amphotericin B 8/37 (21.6%) 10/56 (17.9%)** 12/93 (12.9%) Voriconazole 2/37 (5.4%) Posaconazole 0/37 (0%) 2/56 (3.6%) 2/93 (2.2%) Amphotericin B plus 3/37 (8.1%) 18/56 (32.1%) 21/93 (22.6%) (or followed by azole) 8 (18%) died 11 (18.9%) died 19 (18.6%) died Outcome * Laboratory data are reported only when available. # One patient each from :Nigeria, India, Bangladesh, Italy, The Netherlands; for 1 country was unknown; § One patient each from: India, Ireland, Mali, Oman, Qatar: ** In one case associated with terbinafine 9
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S1477-8939(19)30009-2
DOI:
https://doi.org/10.1016/j.tmaid.2019.01.013
Reference:
TMAID 1378
To appear in:
Travel Medicine and Infectious Disease
Received Date: 21 June 2018 Revised Date:
18 December 2018
Accepted Date: 16 January 2019
Please cite this article as: Pezzani MD, Di Cristo V, Parravicini C, Sonzogni A, Franzetti M, Sollima S, Corbellino M, Galli M, Milazzo L, Antinori S, Gastrointestinal basidiobolomycosis: An emerging mycosis difficult to diagnose but curable. Case report and review of the literature, Travel Medicine and Infectious Disease (2019), doi: https://doi.org/10.1016/j.tmaid.2019.01.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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TMAID-D-18-00147R1
but curable. Case report and review of the literature
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Gastrointestinal basidiobolomycosis: an emerging mycosis difficult to diagnose
Maria Diletta Pezzani 1*§, Valentina Di Cristo 1*, Carlo Parravicini 2, Angelica Sonzogni 3, Marco Franzetti 4^, Salvatore Sollima 4, Mario Corbellino 4, Massimo Galli 1,4, Laura Milazzo 4 , Spinello
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Antinori 1,4
Department of Biomedical and Clinical Sciences “Luigi Sacco”, University of Milano, Italy;
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Institute of Pathology, Luigi Sacco Hospital, Milano, Italy; 3Division of Pathology, Istituto
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Europeo di Oncologia, Milano, Italy; 4 III Division of Infectious Diseases, ASST Fatebenefratelli
Correspondence to : Prof Spinello Antinori
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Sacco, Ospedale L Sacco, Milano, Italy
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Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milano, Italy
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Tel 00390250319765
Email: [email protected] Key words : Basidiobolomycosis ; gastrointestinal infection ; Italy ; emerging mycosis * MDP and VDC contributed equally to this work § Present address. Dipartimento di Diagnostica e Sanità Pubblica, Università di Verona ^ Present address: Medicine Department, Division of Infectious Diseases, A Manzoni Hospital, ASST Lecco
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ACCEPTED MANUSCRIPT Abstract Background: Gastrointestinal basidiobolomycosis (GIB) is a rare mycosis affecting almost exclusively immunocompetent subjects Methods: We describe a case of GIB caused by Basidiobolus ranarum in a 25-year-old Italian
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immunocompetent man resident in Ireland who presented a 2-month history of epigastric pain. Suspecting colon cancer he underwent a right hemicolectomy subsequently leading to a diagnosis of GIB by means of molecular biology. After surgery a 9-month therapy with itraconazole was
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employed with a good outcome. A review of medical literature regarding GIB cases published in the period 1964-2017 is presented.
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Results: One-hundred and two cases of GIB were included in this analysis. The disease was observed predominantly in male gender (74.5%) and children (41.2%). Abdominal pain was the single most common complaint (86.3%) followed by fever (40.2%) and evidence of an abdominal mass (30.4%). Peripheral blood eosinophilia was detected in 85.7% of cases. Most of the patients
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were diagnosed in Saudi Arabia (37.2%) followed by USA (21.6%) and Iran (20.6%). Surgery plus antifungal therapy was employed in the majority of patients (77.5%). An unfavourable outcome was documented globally in 18.6% of patients
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Conclusions: GIB seems to be an emerging intestinal mycosis among immunocompetent patients
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living in the Middle East and Arizona.
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1. Introduction Basidiobolus ranarum was initially described in 1886 as a fungus cultured from frogs and two years later cultured from their intestinal contents and excreta [1]. It was first isolated in 1955 from
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decayed leaves in the United States and subsequently from soil and decaying vegetation from throughout the world [2-5]. It is actually classified in the phylum Entomophthoromycota that includes one of the largest groups of early-diverging terrestrial fungi previously classified in the
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phylum Zygomycota (Table 1) [6,7]. B. ranarum belongs to the class Basidiobolomycetes which includes a single order and family and it is a commensal in the gut of amphibians (frogs, toads), fish
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, reptiles and insectivorous bats [7]. B. haptosporus, B. heterosporos and B. meristosporos have been considered in the past as synonyms of the species B. ranarum [8]. Human disease caused by Basidiobolus was first described as a skin and subcutaneous indolent and slowly progressing infection, affecting the limbs, trunk and buttocks of young males residing in tropical and subtropical
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regions [9-11]. The exact mode of transmission of the fungus has not yet been characterised but in the case of subcutaneous disease, it has been attributed to the more frequent habit (by males) of using decaying plant leaves as toilet paper after defecating in the open or otherwise via minor skin
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trauma and insect bites. However, it remains puzzling how the fungus is introduced into the host’s gastrointestinal tract, thus resulting in gastrointestinal basidiobolomycosis (GIB). It has been
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suggested that ingestion of soil, animal faeces or food contaminated by either might be responsible , explaining the highest number of cases observed among children. The first case of GIB was probably reported in 1964 as an autopsy diagnosis in a 6-year old children from Nigeria who had also subcutaneous lesions [4]. However, Brazilian authors were the first who recognised GIB as a distinct clinical entity affecting immunocompetent individuals [12]. Although considered an extremely rare disease, GIB seems to be an emerging fungal infection in Saudi Arabia, Iran, Iraq and Arizona in the United States of America. We report here a case of GIB observed in a young immunocompetent Italian patient together with a review of the literature. 3
ACCEPTED MANUSCRIPT 2. Materials and methods Definitions We defined a confirmed case of GIB on the basis of either the characteristic histopathologic appearance of the fungus in tissue biopsy or from surgical specimens obtained from gastrointestinal
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organs (i.e., stomach, small intestine, colon, rectum, liver, gallbladder, pancreas) or the isolation of Basidiobolus ranarum from such specimens or identification by molecular methods.
The PubMed and Scopus databases were searched for articles (in English, French, Spanish
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languages) published between 1964 and 2017 using the following combination of MESH terms: basidiobolomycosis AND gastrointestinal; basidiobolomycosis AND abdominal infection;
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Basidiobolus ranarum AND gastrointestinal infection; entomophtoromycosis AND gastrointestinal. Articles were reviewed in detail by 2 of us (M.D.P. and V.D.C.) to determine whether cases met the inclusion criteria. Additional cases were identified by reviewing references. Several cases were
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reported more than once and duplicates were excluded.
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ACCEPTED MANUSCRIPT 3. Results 3. 1 Case report In March 2013, a 25-year-old Italian male was admitted to a specialized oncological institute in Milan, for a suspect bowel neoplasm. He had a history of epigastric and lower right abdominal pain
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over the last two months so he had done on February an US abdomen which showed a mass in the right lumbar-hypogastric region of 65 mm in transverse diameter with associated retroperitoneal lymph nodes. The patient was an otherwise healthy man with an unremarkable past medical history;
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he was living in Cork, Ireland, working as a cook in a hotel.
Physical examination showed no abnormalities except a palpable tender mass on the right lower
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quadrant; on laboratory investigations white blood cell count was 10.1 x 109/L (normal value 4.411.3) with 0.99 x 109/L eosinophils (normal value 0.04-0.4), hemoglobin level of 15.6 g/dL, normal liver function tests, electrolyte levels and creatinine levels. CT scan of the pelvis and lower abdomen showed diffuse circumferential wall thickening affecting distal ileal loop and cecum,
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narrowing of lumen and regional lymph node involvement (Figure 1a). Colonoscopy was performed, revealing a complete stricture of the ascending colon due to an ulcerated mass (Figure 1b). Biopsies were taken and histopathology showed granulomatous and necrotizing inflammation.
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Because of a clinical profile suggestive of malignancy with colonic obstruction a right hemicolectomy was done. At the histology examination there were areas of necrotizing
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inflammation with marked eosinophilic infiltrate and foreign body- type giant cell reaction; fungal hyphae were seen within some of the multinucleated giant cells and a presumptive diagnosis of intestinal zygomycosis was done by the pathologist. The patient was referred to our Infectious diseases ward for further evaluation and management. Upon reviewing the pathology material, the hyphae had few septa, were highlighted by the PAS and Grocott stains and surrounded by eosinophilic and hyaline material (Splendore-Höeppli phenomenon) (Figure 2). The identification of the fungus was established by DNA extraction from formalin-fixed paraffin embedded tissue and panfungal polymerase chain reaction (PCR) 5
ACCEPTED MANUSCRIPT amplification of 18S rRNA. Amplified fragment had 99% identity with Basidiobolus ranarum (13) (Figure 3). Because preoperative diagnosis was presumed to be malignant, no tissue was sent for culture. Pending molecular typing of fungus, the patient was started on liposomal amphotericin B at
and clinical failure with amphotericin B has been described.
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the dose of 5 mg/kg, 4 days later substituted with itraconazole po 200 mg BID because resistance
Immunological deficiencies were excluded by additional investigations (lymphocyte
subpopulations, HIV, HBV, HCV, immunoglobulins, C3 and C4, oxidative BURST, T-lymphocyte
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maturation study and CD11b expression on neutrophils and monocytes). Complete blood count, apart from eosinophilia (12% maximum), was normal as other laboratory results. US abdomen
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before discharge showed hepatosplenomegaly, normal ileal and colic loops without any mass. The patient was discharged in April with oral itraconazole 200 mg BID and regular follow-up was started.
After 3 months abdominal CT was negative. In January 2014 the patient repeated US abdomen,
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showing only splenomegaly, and laboratory tests (white blood cell count 7.4 x 109/L with 0.23 x 109/L eosinophils). He received itraconazole 200 mg x 2/daily for a total of 9 months; at one year
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follow up he is in good health without relapse of the disease.
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3. 2 Review of the literature Gastrointestinal basidiobolomycosis (GIB) has been considered an extremely rare disease with only six cases reported in the literature up to 1994 [4,12,14-16].However, starting from 1995 a cluster of
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cases of GIB was described from Arizona with 19 patients (89 % resident in Arizona) identified between 1995 and 2009 at Mayo Clinic, Scottsdale (Arizona) [17-20 ].Eight of these 19 patients had been described separately before being finally reviewed by Vikram et al. in 2012 together with
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other 25 cases observed outside the United States [21]. All the detailed published cases (with the exception of 12 cases reported in the review by Vikram and not singularly described) plus the one
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observed by us are summarised in table 2 [4,12,14-20, 22-62]. We noted that a further 18 pediatric cases of basidiobolomycosis were reported in 2017 but they are not included in the present review because of the lack of any detailed information regarding single cases [63]. Eleven cases were reported in a 36-year period (1964-2000; a mean of 0.3 cases/year) and 78 in the last seventeen
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years (2001-2017; a mean of 4.6 cases/year) with a 15.3-fold increase. Overall, we considered for the purpose of our review the forty-four cases previously reviewed by Vikram et al. in 2012 plus fifty-eight new cases (including our present observation) described in detail after 2008 [21] (Table
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3). A male prevalence was observed (76/102, 74.5%) with a 3:1 ratio. All but one patient were immunocompetent [59]. The median age was 19 years (range 1-81 years) and 42 patients (41.2%)
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were children (age 1-13 years). The countries of residence in 79.4% of patients were only three: Saudi Arabia (37.2%), USA (21.6%) and Iran (20.6%) (Figure 4). Abdominal pain (86.3%) was the most common presenting symptom followed by weight loss (33.3%), abdominal distension (16.7%), vomiting (15.7%) and diarrhea (13.7%) (Table 3). Fever was reported only in 40.2% of patients and an abdominal mass was palpable in 30.4% of cases. Peripheral blood eosinophilia was detected in 85% of patients for whom this data was available. An initial misdiagnosis was made in 68 % of cases (68/102) with neoplasms and inflammatory bowel disease being the more frequently considered diagnosis (55.8%).In 32 cases (31.4%) the diagnosis was obtained by histopathology 7
ACCEPTED MANUSCRIPT plus culture and/or polymerase chain reaction (PCR), in 66 patients (64.7%) only by histopathology . In four cases the correct diagnosis was achieved only post-mortem. Overall, culture for B. ranarum was positive in 34/53 cases (64.2%). Identification by PCR was obtained in 5 cases. Colon-rectum were involved in 84.2% of cases. On histopathology the presence of fungal hyphae, granulomatous
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inflammation, eosinophilic infiltration together with the Splendore-Höeppli phenomenon observed in the gastrointestinal tract should be considered highly suggestive for B. ranarum. Overall 93/102 (91.2%) patients received an antifungal therapy Surgery plus antifungal treatment was employed in
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(36.4%). Overall death was observed in 18.6% of patients.
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79/102 (77.5%) of patients . Eleven patients received only antifungal treatment of which four died
4. Discussion
Basidiobolus ranarum is an environmental filamentous fungus that belongs to the phylum Entomophthoromycota , class Basidiobolomycetes formerly designated as zygomycetes. Recent
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phylogenetic studies showed that Entomophthromycota is a monophyletic lineage characterized by coenocytic vegetative cells, sporulation by production of infective conidia and production of zygospores capable of survival under unfavourable environmental conditions. Basidiobolus spp.
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form uninucleate cells with extremely large nuclei and had an haploid genome that has been estimated to be 10 times larger (350 Mb) than that of the average size of fungi [64]. The fungus
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grows at 30°C in 2-3 days with yellow-gray flat colonies but after 7-10 days colony become overgrown with mycelia as masses of zygospores. After its initial description by Eidam in 1886 [1], Basidiobolus ranarum was subsequently cultured from intestinal contents of frogs [65] and several other species of amphibians and reptiles, from decaying plant material, from an insectivorous bat (Rhinopoma hardwickei hardwickei) in India and from the faeces of kangaroos in Australia. The disease initially associated with B. ranarum was described in Indonesia in 1956 by Joe et al. [9] as subcutaneous phycomycosis and subsequently the same presentation was identified in other areas of tropical and subtropical climate, especially from 8
ACCEPTED MANUSCRIPT Uganda, Nigeria and Indonesia. In 1964 the first case of gastrointestinal involvement was described in a 6-year old Nigerian boy at postmortem examination [4]. Gastrointestinal basidiobolomycosis (GIB) has been considered an extremely rare disease with only six cases reported up to 1999 [63].. Within the past 2 decades a 15-fold increase in cases of gastrointestinal infection by B. ranarum has
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been reported worldwide. Although most of the cases have been described in the Middle East (Saudi Arabia, Iran, Iraq, Kuwait, Oman, Qatar) [23-26,29,31-39,41-46,48-50,52-55,57,60,62] and the southwestern of United States (Arizona and Utah) [15,17-20,40,47,56], sporadic reports came
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from South America, Africa , Europe and the Indian Subcontinent [4,12,14,16,27,28,30,51, 59,PR] and no clear environmental risk factors have been identified. In the case-control study performed by
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Lyon et al. in Arizona, ranitidine use (OR 6.0) and a longer period of smoking (OR 2.1/additional 20 years of smoking) were both associated with the development of the disease [20]. It has been hypothesized that the decreased gastric acidity together with the alteration of white blood cells activity induced by smoking might contribute to the survival of ingested B. ranarum. However,
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rural environment and activities such as gardening and landscaping as well as ingestion of contaminated soil or fruits and vegetables seem to be associated with a higher risk of exposure to the infection [21]. Since B. ranarum usually involves immunocompetent subjects, factors
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associated with health history of the hosts are not helpful for the diagnosis that is therefore frequently delayed. Of the three patients reported in Europe [27,30, PR], only the one described
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here was diagnosed during life. However, at least in endemic areas, a higher awareness of GIB by clinicians might partially account for the increase in the number of cases reported in the last decades. As in previous cases, in our patient the route of acquisition of the disease remains unknown; however since B. ranarum can be found in soil and decaying vegetables, we hypothesized that the consumption of homebrew unpasteurized and unfiltered beer might have been the source of fungal ingestion and subsequent involvement of the intestine. A preliminary misdiagnosis among patients with GIB was commonly reported in the literature, the most frequent being gastrointestinal malignancy and inflammatory bowel diseases 9
ACCEPTED MANUSCRIPT [17,22,30,33,34,36,37,41,42,56,61,62, PR], although a suspicion should be raised whenever fever and abdominal pain occur in young patients with gastrointestinal, abdominal mass or intestinal wall thickening in association with high eosinophilia. Although a definite diagnosis can be obtained with culture [14,15,18,19,22-
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24,30,33,35,41,45,47,49-51,54,59,62], it was frequently missed in previous reports because of the lack of suspicion that made tissue specimens unavailable for culture purpose. Therefore, the diagnosis of gastrointestinal infection by B. ranarum was mainly obtained on histologic
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examination, which typical morphologic features include granulomatous inflammation and a diffuse eosinophilic infiltrate with thin walled branched hyphae surrounded by eosinophilic material
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(Splendore-Höeppli phenomenon) and sometimes zygospores (spherical bodies with foamy cytoplasm) [4,6,12,16,17,20,24,26-29,31-33,35-39,42-44,46,49,52,53,55,58,60,61]. The immunodiagnostic test such as immunodiffusion is not standardized yet, since it showed a high specificity but a controversial sensitivity [20]. Finally, since suitable specimens for culture purpose
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are often unavailable, molecular diagnosis from formalin fixed paraffin embedded tissue represents the optimal adjunctive diagnostic method to histology, as it showed a high specificity and high sensitivity [34,40,51,54,PR].
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Treatment of GIB usually requires a combination of surgical and medical approach. Surgical resection of infected bowel tissues must be followed by itraconazole for at least 6 months to prevent
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recurrence. There are also a few cases described in the literature that showed a successful outcome with antifungal treatment alone [33-35, 42,56,61]. The role of amphotericin B has been overcome since resistance has been observed in more than 50% of cases [25]. Potassium iodide (KI) has been traditionally used for the treatment of subcutaneous basidiobolomycosis and more recently it was employed successfully in a single case report of a child with GIB [21,66,67]. However, as suggested by Bering et al., the absence of demonstrable in vitro activity of KI against B. ranarum coupled with several possible limitations (toxicity associated with high doses, lack of any standard prescription recommendation, available new azoles) do not recommend its use in GIB [68]. More 10
ACCEPTED MANUSCRIPT recently successful treatments with voriconazole [42,49,50,53-55,58,59] and posaconazole [40,48,50] have been reported. On the basis of the experience reported in the literature azoles should be considered the drugs of choice for GIB. 5. Conclusions
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In conclusion, GIB should be suspected in patients complaining abdominal pain associated with gastrointestinal and/or colon mass who has concomitant peripheral eosinophilia especially if they come from the Middle-East or arid zone from USA. Moreover, the observation of the Splendore-
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Höeppli phenomenon (although not pathognomonic being associated with several microorganisms) [69] in the presence of zygomicetes in tissue samples from immunocompetent patients should raise
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the suspicion of basidiobolomycosis and confirmation by using molecular diagnosis should be sought through pathologists able to do it. Although some reports indicate successful outcome by using only medical therapy, surgery with resection of affected bowel segments associated with prolonged antifungal treatment should be advised. Itraconazole seems to be the best available
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treatment although other new azoles have also been successfully employed. The exact length of
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duration of antifungal therapy remains to be established.
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ACCEPTED MANUSCRIPT References [1] Eidam E. Basidiobolus, eine neue Gattung der Entomophthoraceen. Beitrage Biol Pflanzen 1886;4:181-251.
elongated adhesive conidia. J Wash Acad Sci 1955;45:49-56.
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[2] Drechsler C. A southern basidiobolus forming many sporangia from globose and from
[3] Drechsler C. Supplementary developmental stages of Basidiobolus ranarum and Basidiobolus haptosporus. Mycologia 1956;655-76.
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[4] Edington GM. Phycomycosis in Ibadan, Western Nigeria. Trans R Soc Trop Med Hyg 1964; 58:242-45.
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[5] Clark, B. M. Epidemiology of phycomycosis. In G. E. W. Wolstenhome and R. Porter (ed.), Systemic mycoses. Little, Brown & Co., Boston, Mass,1968: 179-192. [6] Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease. Clin Microbiol Rev 2000;13:236-301.
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[7] Gryganskyi AP, Humber RA, Smith ME, Hodge K, Huang B, Voigt K, et al. Phylogenetic lineages in Entomophthoromycota. Persoonia 2013;30:94-105. [8] Coremans-Pelseneer, J. Isolation of Basidiobolus meristosporus from natural sources.
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Mycopathol Mycol Appl 1973;49:173–76.
[9] Joe LK, Eng NIT, Pohan A, van der Muillen H, Emmons CW. Basidiobolus ranarum as a
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cause of subcutaneous mycosis in Indonesia. Arch Dermatol 1956;74:378-383. [10] Burkitt DP, Wilson AMM, Jelliffe DB. Subcutaneous phycomycosis: a review of 31 cases in Uganda. Br Med J 1964;1:1669-72. [11] Mugerwa JW. Subcutaneous phycomycosis in Uganda. Br J Dermatol 1976; 94: 539-44. [12] Bittencourt AL, Ayala M, Ramos EAG. A new form of abdominal zygomycosis different from mucormycosis. Am J Trop Med Hyg 1979; 28:564-569. [13] El-Shabrawi MH, Kamal NM, Kaerger K, Voigt K. Diagnosis of gastrointestinal basidiobolomycosis: a mini-review. Mycoses. 2014;57 Suppl 3:138-43. 12
ACCEPTED MANUSCRIPT [14] de Aguiar E, Moraes WC, Londero AT. Gastrointestinal entomophthoramycosis caused by Basidiobolus haptosporus. Mycopathologia 1980; 72:101-5. [15] Schmidt JH, Howard RJ, Chen JL, Pierson KK. First culture-proven gastrointestinal entomophthoromycosis in the United States: a case report and review of the literature.
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Mycopathologia 1986; 95:101-4.
[16] Carvalho FA, de Macedo JL, Costa JN, Moraes MA. Entomoftoromicose intestinal : relato de caso. Rev Soc Brasil Med Tropical 1997; 30:65-68.
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[17] Pasha TM, Leighton JA, Smilack JD, Heppell J, Colby TV, Kaufman L.
Gastroenterology 1997; 112:250-54.
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Basidiobolomycosis: an unusual fungal infection mimicking inflammatory bowel disease.
[18] Centers for Disease Control and Prevention. Gastrointestinal Basidiobolomycosis: Arizona. MMWR Morb Mortal Wkly Rep 1999;48:710-4
[19] Zavasky D-M, Samowitz W, Loftus T, Segal H, Carroll K. Gastrointestinal zygomycotic
28: 1244-48.
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infection caused by Basidiobolus ranarum: case report and review. Clin Infect Dis 1999;
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Gastrointestinal basidiobolomycosis in Arizona: clinical and epidemiological characteristics and review of the literature. Clin Infect Dis 2001; 32:1448-55.
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ACCEPTED MANUSCRIPT [23] Khan ZU, Khoursheed M, Makar R, Al-Waheeb S, Al-Bader L, Al-Muzaini A, et al. Basidiobolus ranarum as an etiologic agent of gastrointestinal zygomycosis. J Clin Microbiol 2001; 39: 2360-63. [24] Al Jarie A, Al-Mohsen I, Al Jumaah S, Al Hazmi M, Al Zamil F, Al Zaharani M, et al.
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Pediatric gastrointestinal basidiobolomycosis. Pediatr Infect Dis J 2003; 22:1007-13.
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[26] Azadeh B, McCarthy DO’B, Dalton A, Campbell F. Gastrointestinal zygomycosis: two
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[27] Bigliazzi C, Poletti V, Dell’Amore D, Saragoni L, Colby TV. Disseminated basidiobolomycosis in an immunocompetent woman. J Clin Microbiol 2004; 42: 1367-1369. [28] Vianna LM, de Lacerda MV, de Moraes MA. Case report of subcutaneous entomophthoromycosis with retroperitoneal invasion. Rev Soc Bras Med Trop.2005; 38:348-50.
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[29] Fahimizad A, Karimi A, Tabatabaei SR, Zadeh MG. Gastrointestinal basidiobolomycosis as a rare etiology of bowel obstruction. Turk J Med Sci 2006; 36: 239-241. [30] van de Berk GE, Noorduyn LA, van Ketel RJ, van Leeuwen J, Bemelman WA, Prins JM.
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A fatal pseudo-tumor: disseminated basidiobolomycosis. BMC Infect Dis 2006; 6:140. [31] Hussein MR, Musalam AO, Assiry MH, Eid RA, El Motawa A-M, Gamel A-M.
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Histological and ultrastructural features of gastrointestinal basidiobolomycosis. Mycol Res 2007;111:926-30.
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ACCEPTED MANUSCRIPT [34] El-Shabrawi MHF, Kamal NM, Jouini R, Al-Harbi A, Voigt K, Al-Malki T. Gastrointestinal basidiobolomycosis: an emerging fungal infection causing bowel perforation in a child. J Med Microbiol 2011;60:1395-1402.
Basidiobolomycosis: case series. J Mycol Med 2011; 21:37-45
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[35] Al Jarie A, Al Azraki T, Al Mohsen I, Al Jumaah S, Almutawa A, Mohd Fahim Y, et al.
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[37] Saadah OI, Farouq MF, Daajani NA, Kamal JS, Ghanem AT. Gastrointestinal
basidiobolomycosis in a child: an unusual fungal infection mimicking fistulising Crohn’s
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disease. J Crohn’s Colitis 2012, 6:368-72.
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[39] Geramizadeh B, Foroughi R, Keshtkar-Jahromi M, Malek-Hosseini SA, Alborzi A.
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Gastrointestinal basidiobolomycosis, an emerging infection in the immunocompetent host: a report of 14 patients. J Med Mycol 2012; 61:1770-4. [40] Rose SR, Lindsley MD, Hurst SF, Paddock CD, Damodaran T, Bennett J. Gastrointestinal
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basidiobolomycosis treated with posaconazole. Med Mycol Case Rep 2013;2:11-14. [41] Al Asmi MM, Faqeehi HY, Alshahrani DA, Al-Hussaini AA. A case of pediatric
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gastrointestinal basidiobolomycosis mimicking Crohn’s disease. Saudi Med J 2013;34:1068-72. [42] Al Saleem K, Al-Mehaidib A, Banemai M, Bin-Huassain I, Faqih M, Al Mehmadi A. Gastrointestinal basidiobolomycosis: mimicking Crohn’s disease case report and review of the literature. Ann Saudi Med 2013;33: 500-504. [43] Zahir ST, Sharahjin NS, Kargar S. Basidiobolomycosis a mysterious fungal infection mimic small intestinal and colonic tumour with renal insufficiency and ominous outcome. BMJ Case Rep 2013; doi10.1136/bcr-2013-200244.
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ACCEPTED MANUSCRIPT [44] Hassan HA, Majid RA, Rashid NG, Nuradeen BE, Abdulkarim QH, Hawramy TA, et al. Eosinophilic granulomatous gastrointestinal and hepatic abscess attributable to basidiobolomycosis and fascioliasis. A simultaneous emergence in Iraqui Kurdistan. BMC Infect Dis 2013;13:91.
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[45] Alshehri AH, Alshehri A, Bawahab MA, Al-Humayed S, Nabrawi K, Alamri FS, et al. Basidiobolomycosis: an emerging fungal infection of the gastrointestinal tract in adults. Am J Infect Dis 2013;9:1-6.
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[46] Al-Qahtani SM, Alsuheel AM, Shati AA, Mirza NI, Al-Qahtani AA, Al-Hanshani AA, et al. Case reports: gastrointestinal basidiobolomycosis in children. Curr Pediatr Res 2013;7:1-6.
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[47] Pandit V, Rhee P, Aziz H, Jehangir Q, Friese R, Joseph B. Perforated appendicitis with gastrointestinal basidiobolomycosis: a rare finding. Surg Infect 2014, 15:339-42. [48] Zabolinejad N, Naseri A, Davoudi Y, Joudi M, Aelami MH. Colonic basidiobolomycosis in a child: report of a culture – proven case. Int J Infect Dis. 2014 ;22:41-3
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[49] Alahmadi R, Sayadi H, Badreddine H, Linijawi A, Baatrup G, Al-Maghrabi J. Gastrointestinal basidiobolomycosis, the experience of a tertiary care hospital in the western region of Saudi Arabia and report of four new cases. Life Sci J 2014;11:344-352.
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[50] Al-Maani AS, Paul G, Jardani A, Nayar M, Al-Lawati F, Al-Baluishi S, Hussain IB. Gastrointestinal basidiobolomycosis. First case report from Oman and literature review. Sultan
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Qaboos University Med J 2014;14:e241-44. [51] Cazorla A, Grenouillet F, Piton G, Faure E, Delabrousse E, Mathieu P, et al. Une forme gastro-intestinale de basidiobolomycose d’evolution fatale. Ann Pathol 2014;34:228-32. [52] Ejtehadi F, Anushiravani A, Bananzadeh A, Geramizadeh B. Gastrointestinal basidiobolomycosis accompanied by liver involvement: a case report. Iran Red Crescent Med J 2014;16:e14109.
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ACCEPTED MANUSCRIPT [53] Albaradi BA, Babiker AM, Al-Qahtani HS. Successful treatment of gastrointestinal basidiobolomycosis with voriconazole without surgical intervention. J Trop Pediatr 2014; 60:476-9. [54] Alhuraiji A, Alqaraawi A, Alaraj A, Al-Abdely HM, Alrajhi AA. Chronic abdominal pain
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and intestinal obstruction in a 24-year-old woman. Clin Infect Dis 2014;58:990;1035.
[55] Al-Naemi AQ, Ali Khan L, Al-Naemi I, Amin K, Ali Athlawy Y, Awad A, et al. A case
Medicine 2015;94:e1430.
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report of gastrointestinal basidiobolomycosis treated with voriconazole. A rare emerging entity.
[56] Ilyas MI, Jordan SA, Nfonsam V. Fungal inflammatory masses masquerading as colorectal
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cancer: a cse report. BMC Res Notes 2015;8:32.
[57] Geramizadeh B, Sanai Dashti A, Kadivar MR, Kord S. Isolated hepatic basidiobolomycosis in a 2-year old girl: the first case report. Hepat Mon 2015;15:e30117. [58] Mandhan P, Hassan KO, Samaan SM, Ali MJ. Visceral basidiobolomycosis: an
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overlooked infection in immunocompetent children. Afr J Paediatr Surg 2015;12:193-6. [59] Sethi P, Balakrishnan D, Surendran S, Umer Mohamed Z. Fulminant zygomycosis of graft
2015-214097.
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liver following liver transplantation. BMJ Case Rep 2016; pii: bcr2015214097. doi:10.1136/bcr-
[60] Ageel HI, Arishi HM, Kamli AA, Hussein AM, Bhavanarushi S. Unusual presentation of
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Gastrointestinal Basidiobolomycosis in a 7-year-old Child – Case Report. Am J Med Case Rep 2017;5:131-4.
[61] Almoosa Z, Alsuhaibani M, Aidandan S, Alshahrani D. Pediatric gastrointestinal basidiobolomycosis mimicking malignancy. Med Mycol Case Rep 2017,18:31-33. [62] Zekavat OR, Abdalkarimi B, Pouladfar G, Fathpour G, Mokhtari M, Shakibazad N. Colonic basidiobolomycosis with liver involvement masquerading as gastrointestinal lymphoma: a case report and literature review. Rev Soc Bras Med Trop 2017;50:712-4.
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ACCEPTED MANUSCRIPT [63] Shreef K, Saleem M, Saeedd MA, Eissa M. Gastrointestinal Basidiobolomycosis: An Emerging, and A Confusing, Disease in Children (A Multicenter Experience). Eur J Pediatr Surg 2018;28:194-9. [64] Henk DA, Fisher MC. The gut fungus Basidiobolus ranarum has a large genome and
2012;7(2):e31268.
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different copy numbers of putatively functionally redundant elongation factor genes. PLoS One.
[65] Sutherland-Campbell H. An attempt to prove the etiologic factor in an epidemic among
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orange workers. Arch Dermatol Syphilol 1929; 19:233–254.
[66] Sanaei Dashti A, Nasimfar A, Khorami HH, Pouladfar G, Kadivar MR, Geramizadeh B, et
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al. Gastro-intestinal basidiobolomycosis in a 2-year-old boy: dramatic response to potassium iodide. Paediatr Int Child Health 2018, 38:150-3.
[67] Vilela R, Mendoza L. Human pathogenic Entomophthorales. Clin Microbiol Rev 2018;31:e00014-18.
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[68] Bering J, Mafi N, Vikram HR. Basidiobolomycosis: an unusual, mysterious, and emerging endemic fungal infection. Paediatr Int Child Health 2018;38:81-4.
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[69] Gopinath D. Splendore-Höeppli phenomenon. I Oral Maxillofac Pathol 2018;22:161-2.
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ACCEPTED MANUSCRIPT Figure legends Figure 1. Computed tomography scan showing a mass in the ascending colon Figure 2. (A,B) Histopathologic section of colon showing granumomatous inflammation of the colonic wall with prominent eosinophilic infiltrate with a transversely cut hypha (black arrow)
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surrounded by an intensely eosinophilic cuff (Splendore-Hoeppli phenomenon, white arrow) (Hematoxylin-eosin x100 and x400). (C,D) Detailed view of large fungal hypha surrounded by eosinophilic Splendore-Hoeppli material and numerous eosinophils and polymorphonuclear
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leucocytes (E&E x 400).
Figure 3. Panfungal PCR that amplifies the internal transcriber space (ITS) region of the rDNA
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gene performed on multiple samples (F,B1,C3,A2) of paraffin-embedded tissue specimens from different areas of the mass. Sequenced amplicons gave a 99% matching with Basidiobolus ranarum (One µg and 100 nanograms, respectively were tested).
Figure 4. Geographical distribution of cases of 101 gastrointestinal basidiobolomycosis reported
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worldwide (for one case the country was unknown).
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Table 1- Taxonomic classification of Basidiobolus ranarum within Entomophthoromycota phylum Previous Zygomycota
Actual Entomophthoromycota
Class
Zygomycetes
Basidiobolomycetes
Order
Entomophthorales
Basidiobolales
Family
Basidiobolaceae
Basidiobolaceae
Species
Basidiobolus
B. ranarum; B. haptosporus; B. heterosporus; B. magnus; B. meristoporus; B. microsporus ( plus undescribed new genera)
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Taxonomy Phylum
1
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Table 2. Chronological summary of 89 case reports of gastrointestinal basidiobolomycosis Age/sex
Clinical presentation
Leukocyte/Eosinophils/ Splendore-Hoeppli phenomenon NR/NR/NR
Organ involvement
Diagnosis
Therapy
Outcome
Nigeria
6/M
2/12
1977/1979
Brazil
13/M
3/12
NR/1979
Brazil
60/M
Subcutaneous lesions (penis, scrotum, perineum); bloody diarrhea Abdominal pain, fever, weakness, anorexia Abdominal pain
I; C; R; bladder
Post-mortem (histopathology)
Colostomy; antibiotics
Death
NR/16%/Yes
S; D; L; P; C; BT S; C
Post-mortem (histopathology) Histopathology; culture negative
Laparatomy
Death 11 days after surgery Cured
4/14
1979/1980
Brazil
4/M
Fever, abdominal pain, sweats, diarrhea
13,500 µL/26%/Yes
S; C
19,500 µL/6%/Yes
I; Ce; C
Histopathology; culture (Basidiobolus haptosporus) Histopathology/culture (B.haptosporus/ranarum)
12,600 µL/11%/Yes
I; Ce; C:
Histopathology
Surgery/
Death 12 days after surgery (peritonitis) Death 4 weeks after laparotomy NR
5/15
NR/1986
USA
69/M
6/16
1989/1997
Brazil
19/M
7/17
1994/1997
USA
49/F
8/22
1996/1998
Kuwait (Bangladesh)
30/M
Fever, abdominal pain, nausea, constipation, vomiting, right lower quadrant mass Fever, abdominal mass, weight loss, sweats Abdominal and rectal pain, constipation followed by mucus and bloody diarrhea Rectal bleeding, constipation, rectal mass
23,400 µL/NR)/Yes
C; R
Histopathology/serology
Surgery/Itracona zole (5 months)
Alive after 13 months
18-22,000 µL/NR/NR
R
Histopathology/Culture (B.ranarum)/serology
Lost to followup
26,400 µL/10%/NR
S; P
Histopathology
12,100 µL/6%/NR
C
16,400 µL/8%/ Yes
S ; C ; R; ureter
Histopathology/Culture (B.ranarum) Histopathology/Culture (B.ranarum)
Abdominal pain, abdominal mass
NR/NR/Yes
I ; Ce ; appendix ; retroperitone um
Histopathology/Culture (B.ranarum)
Surgery/AmB (3weeks)+ketoco nazole (1 week) Surgery/Itracona zole (9.5 months) Surgery/Itracona zole Surgery/AmB (1week)+ itraconazole (11 months) ; terbinafine 2 months Surgery/Itracona zole (19 months)
9/18
1998/1999
USA
37/F
Abdominal pain
10/ 18
1998/1999
USA
59/M
11/19
1997/1999
USA
57/M
Abdominal pain, mucus, colonic obstruction Abdominal pain, anorexia, fatigue, constipation
12/20
1996/2001
USA
46/M
13/20
1998/2001
USA
52/M
Abdominal pain
12,800 µL/14,3%/Yes
C
Histopathology/ culture negative/serology
Surgery/Itracona zole (10 months)
14/20
1999/2001
USA
59/M
Abdominal pain, constipation
NR/NR/NR
Ce; C
41/M
Fever, abdominal pain,
NR/NR/Yes
Ce; C
Histopathology/Culture not done Histopathology/Culture
Surgery/Itracona zole (10 months) Surgery/LAmB
15/23
1999/2001
Kuwait
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Country
1/4
Year observation/ Publication NR/1964
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NR/NR/Yes
AC C
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Patient/Reference
Gastrectomy & hemicolectomy; AmB Surgery
Surgery/AmB
Cured
Cured Cured
Alive (31 months ; 12 months after itraconazole withdrawal) Alive 4 months after itraconazole withdrawal) Alive Lost to follow-
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I; Ce; C; L; BT
11,000 µL/20%/Yes
I; Ce; C
Histopathology
18/ 24
2001/2003
Saudi Arabia
9/M
Fever, abdominal pain
17,800 µL/19.8%/NR
19/ 24
2002/2003
Saudi Arabia
4/M
Fever, abdominal pain, hepatomegaly
30,000 µL/30%/NR
20/ 24
2001/2003
Saudi Arabia
3/M
Fever, abdominal pain, heaptomegaly, ascites
24,500µL/18%/Yes
21/ 24
2000/2003
Saudi Arabia
7/M
16,900 µL/17%/Yes
22/25
NR/2003
Saudi Arabia
12/M
17,900 µL/20%/Yes
I; Ce; C
Histopathology/Culture (B.ranarum)
Surgery/Itracona zole (10 months)
Alive
23/26
NR/2004
Iran
45/M
Fever, abdominal pain, abdominal distension, hepatosplenomegaly Fever, abdominal pain, anorexia, weight loss, vomiting, constipation Abdominal pain
NR/NR/Yes
Ce; L
Histopathology
Alive
24/27
NR/2004
Italy
40/F
Fever, subcutaneous lesions
28,320 µL/30%/Yes
Post-mortem (histopathology)
25/28
1990/2005
Brazil
43/M
10,800 µL/NR/Yes
Histopathology
26/29
NR/2006
Iran
1.5/M
Fever, abdominal pain, vomiting, weight loss Fever, abdominal pain, diarrhea, hematochezia
L; P; S; M; lung; spleen; kidneys; uterus P
Surgery/Ketocon azole+cotrimoxa zole (4 weeks) -
NR/Yes/Yes
R
Histopathology
27/30
NR/2006
The Netherlands
61/M
NR/27.7%/Yes
C; L; gallbladder
Histopathology; culture post-mortem B.ranarum
28/31
NR/2007
Saudi Arabia
13/M
Abdominal pain, tenderness
NR/NR/Yes
C
29/32
Iran
18/M
Abdominal pain, constipation
12,000 µL/8%/Yes
I
Iran
2.5/M
C
Histopathology
Iran
2/M
29,400 µL/ 16%/Yes
C
Histopathology
32 /33
2000/2009
Saudi Arabia
77/M
Abdominal pain, constipation, rectal bleeding Abdominal pain, distension, ascites Abdominal pain, abdominal mass, weight loss, rectal bleeding
26,800 µL/10%/Yes
31 / 32
20022007/2007 20022007/2007 2002/2007
Histopathology/Culture negative Histopathology
Normal/NR/Yes
Ce; C
Histopathology
30 / 32
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Saudi Arabia
M AN U
2001/2003
TE D
17/ 24
12/M
Abdominal pain, constipation
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16,000 µL/15%/Yes
12/M
Fever, abdominal pain, abdominal mass, scrotal swelling Fever, abdominal pain
from urine (B.ranarum)/serology Histopathology/Culture (B.ranarum)
EP
2000/2003
abdominal mass
AC C
16/24
(Indian patient) Saudi Arabia
Ce; C; R
L; intestine
L
R; D; BT
Histopathology/Culture (B.ranarum) Histopathology/Culture (B.ranarum) from liver biopsy Histopathology/Culture (B.ranarum) from liver biopsy Histopathology (liver biopsy)
(4 weeks)
up
Surgery/Itracona zole (> 24 months) Surgery/AmB than itraconazole (12 months) Surgery/Itracona zole (10 months) AmB than itraconazole (> 12 months) AmB+5Flu
Alive
AmB+itraconazo le (12 months)
Surgery/ketocon azole (35 days) Surgery/AmB (1 week) than itraconazole (9 months) Cholangiodrain/ AmB
Surgery/Itracona zole Surgery/Itracona zole Surgery/Itracona zole Surgery/Itracona zole Surgery/Itracona zole (2 weeks)
Alive
Alive Alive
Death of MOF 2 days after admission Death (massive GI bleeding)
Death due shock and pulmonary failure Follow-up not stated Alive
Death due to MOF few days after start antifungal therapy Alive Alive (7 years) Alive (10 years) Alive (7 years) Lost to followup
3
33/33
2001/2009
Saudi Arabia
19/F
Fever, abdominal pain, weight loss
NR/NR/Yes
Ce; C
Histopathology/ Culture (B. ranarum)
34 /33
NR/2009
Saudi Arabia
20/M
NR/NR/Yes
C
35/34
NR/2011
Saudi Arabia
10/M
Abdominal mass, weight loss, ematochezia Fever, abdominal pain, vomiting
12,200 µL/17%/Yes
Ce;
36/35
2003/2011
Saudi Arabia
6/M
32,700 µL/11%/NR
37/ 35
2003/2011
Saudi Arabia
13/F
Fever, abdominal pain, abdominal mass Fever, abdominal pain
I; Ce; C
Histopathology/ Culture (B. ranarum) Histopathology/ PCR (B.ranarum) Histopathology/ Culture (B.ranarum) Histopathology
38/ 35
2003/2011
Saudi Arabia
8/F
Fever, anorexia, abdominal distension, weight loss
13,800 µL/4%/Yes
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ACCEPTED MANUSCRIPT
P; L; BT
Histopathology
39/36
NR/2011
Saudi Arabia
25/F
12,800 µL/NR/Yes
C
Histopathology
40 /37
2010/2012
Saudi Arabia
2/M
14,000 µL/19%/Yes
I; Ce; C
Histopathology
41/38
NR/2012
Iran
12/M
Abdominal pain, weight loss, nausea, rectal bleeding Fever, abdominal pain, abdominal mass, vomiting , diarrhea Fever, abdominal pain, vomiting, bloody diarrhea
28,100 µL/16%/Yes
C
Histopathology
42/39
20082012/2012
Iran
1.3/F
Abdominal pain, distension
23,000 µL/17%/Yes
S; C; M
Histopathology/Culture negative
Itraconazole (12 months) AmB than itraconazole Surgery/AmB+it raconazole (12 months) Surgery/AmB than itraconazole (18 months) Surgery/Itracona zole AmB than voriconazole (12 months) Surgery/AmB (1 week) than posaconazole Surgery/AmB than itraconazole
43/ 39
20082012/2012 20082012/2012 20082012/2012 20082012/2012 20082012/2012
Iran
5/M
Abdominal pain, weight loss
21,300 µL/20%/Yes
C
Iran
5/M
Abdominal pain
16,100 µL/10%/Yes
C
Iran
2/M
Abdominal pain, diarrhea
17,400 µL/20%/Yes
I; C
Iran
16/M
Abdominal pain
11,500 µL/14%/Yes
C
Iran
1.3/M
Abdominal pain, diarrhea
18,200 µL/8%/Yes
S; I; C; M
Histopathology/Culture negative Histopathology/Culture negative Histopathology/Culture negative Histopathology/Culture negative Histopathology/Culture negative
Surgery/AmB than itraconazole Surgery/AmB than itraconazole Surgery/AmB than itraconazole Surgery/AmB than itraconazole Surgery/AmB than itraconazole
20082012/2012 20082012/2012 20082012/2012 20082012/2012 20082012/2012 NR/2013
Iran
1.1/M
Abdominal pain, bloody stool
23,000 µL/16%/Yes
C
Iran
37/M
Abdominal pain
20,000 µL/10%/Yes
C
Iran
28/M
Abdominal pain
14,000 µL/10%/Yes
C
Iran
52/M
17,000 µL/15%/Yes
C
Iran
42/F
Abdominal pain, vomiting, diarrhea Abdominal pain
17,000 µL/15.9%/Yes
I; C
USA
67/M
Abdominal pain
NR/NR/Yes
I
Histopathology/Culture negative Histopathology/Culture negative Histopathology/Culture negative Histopathology/Culture negative Histopathology/Culture (B.ranarum) Histopathology/ PCR (B.ranarum)
Surgery/AmB than itraconazole Surgery/Itracona zole Surgery/Itracona zole Surgery/Itracona zole Surgery/Itracona zole Surgery/Ureteral stent/Fluconazol
47/ 39
48 / 39 49/ 39 50 / 39 51 / 39 52 / 39 53 /40
SC
M AN U
TE D
46 / 39
EP
45 / 39
AC C
44 / 39
14,500 µL/18%/Yes
Ce; C; L
LAmB+itracona zole; ketoconazole (4 years) Voriconazole
Alive (4 years)
Alive Alive (1 year) Alive (2 years) Alive (2 years)
Alive 2,5 years) Alive Alive (1 year)
Follow-up not stated Death due to disseminated disease Alive (8 months) Alive (3 years) Alive (6 months) Alive (2 years) Death due to disseminated disease (1,5 months) Alive (1 year) Alive (6 months) Alive (2 years) Alive (6 months) Alive (1year) Alive (2 years)
4
ACCEPTED MANUSCRIPT
NR/2013
Saudi Arabia
4/M
Fever, abdominal pain, vomiting, weight loss
17,000 µL/13.6%/Yes
55 /42
NR/2013
Saudi Arabia
5/M
15,600 µL/15%/Yes
56 /43
NR/2013
Iran
12/M
Fever, abdominal pain, bloody diarrhea, anorexia, weight loss Fever, abdominal pain , hematuria
57/44
2010/2013
Iraq
48/M
58 /44
2010/2013
Iraq
1.5/M
59 / 44
2010/2013
Iraq
59/M
60 / 44
2012/2013
Iraq
53/M
61/ 44
2012/2013
Iraq
39/M
62 / 44
2012/2013
Iraq
1.5/M
63 /45
NR/2013
Saudi Arabia
24/M
64 / 45
NR/2013
Saudi Arabia
21/F
65 / 45
NR/2013
Saudi Arabia
72/M
66 / 45
NR/2013
Saudi Arabia
19/M
67 /46
20092012/2013 20092012/2013
Saudi Arabia
12/F
Saudi Arabia
1.5/M
Saudi Arabia
9/F
70/47
20092012/2013 NR/2013
USA
34/F
71/48
NR/2013
Iran
3/M
69/ 46
Ce; C; L
Histopathology
NR
Histopathology
NR/No/Yes
Ce
Histopathology
NR/NT/Yes
Ce; C
Histopathology
NR/9%/Yes
O; C
Histopathology
NR/21%/Yes
Ce; C
Histopathology
14,400 µL/22%/NR
I; Ce; C
Histopathology/ Culture (B.ranarum) Histopahology/Culture (B.ranarum)
Surgery/Itracona zole (6 months) Surgery/Itracona zole (6 months) Surgery/Itracona zole (7 months) Surgery/Itracona zole (4 months) Surgery/Itracona zole (12 months) Steroid/Itraconaz ole
SC
M AN U
NR/29%/Yes
EP
TE D
Fever, abdominal pain, weight loss, abdominal mass Fever, abdominal pain, weight loss, Fever, weight loss, cough, sore throat Fever, abdominal pain, abdominal mass, weight loss Fever, abdominal pain, weight loss, diarrhea Fever, abdominal pain, diarrhea alternate with constipation, weight loss Fever, abdominal mass
Fever, abdominal pain, abdominal mass
AC C
68 / 46
I; C
NR/12%/Yes
Fever, abdominal pain, constipation Fever, hepatomegaly
Abdominal pain, constipation, vomiting Abdominal pain, constipation, vomiting, weight loss Abdominal pain, abdominal mass
C
Histopathology/ Culture (B.ranarum) Histopathology/Culture negative Histopathology
14,500 µL/No/Yes
Fever, abdominal pain, weight loss Fever, abdominal pain, weight loss, abdominal mass
I; Ce; C
RI PT
54 /41
e (several months); posaconazole 600 (1 year) Surgery/Voricon azole (12 months) Voriconazole (6 months) Surgery/Itracona zole + AmB (2 weeks) then itraconazole Surgery/Itracona zole (6 months) AmB
7,100 µL/No/NR
Ce; C; R
15,280 µL/No/NR
Ce; C
Histopahology/Culture (B.ranarum)
Surgery/Itracona zole
22,100 µL/6.65%/NR
Ce; C
Histopahology/Culture (B.ranarum)
Surgery/Itracona zole
17,600µL/35%/Yes
I; Ce
Histopathology
24,520 µL/10.2%/Yes
L
Histopathology
Surgery/Itracona zole Surgery/Itracona zole
17,800 µL/14%/Yes
C
Histopathology
13,000 µL/16.9%/NR
I; Ce
Histopahology/Culture (B.ranarum)
12,500 µL/6%/Yes
C
Histopahology/Culture (B.ranarum)
Surgery/Itracona zole (8 months) Surgery/Itracona zole+ LAmB (6 weeks) Surgery/Posacon azole (3 months)
Alive (1 year)
Alive (6 months) Death for septic shock
Alive (1 year) Death for intestinal perforation Alive (> 1 year) Alive (10 months) Alive (7 months) Alive (4 months) Alive (1 year) Death for HCassociated infection Death for bowel perforation and ARDS, septic shock (32 days post-surgery) Death for HCassociated infection Alive Death for ARDS after few days Alive (8 months) Alive
Alive (15 months)
5
ACCEPTED MANUSCRIPT
2001/2014
Saudi Arabia
43/M
Abdominal pain, weight loss
15,000 µL/27%/Yes
Ce; C; L
73 / 49
2005/2014
Saudi Arabia
20/F
NR/NR/NR
C
74 / 49
2008/2014
Saudi Arabia
63/M
Abdominal pain, abdominal mass Abdominal pain, weight loss
12,400 µL/14%/Yes
I; C
75 / 49
2011/2014
Saudi Arabia
20/F
Rectal bleeding
14,000 µL/20%/Yes
76 /50
2012/2014
Oman
5/F
Abdominal pain, nausea, vomiting, low grade fever
14,200 µL/50%/Yes
77/51
2014
Mali/France
55/M
Abdominal pain
NR/NR/Yes
78/52
2012/2014
Iran
41/F
79/53
2014
Saudi Arabia
11/M
Abdominal pain, weight loss, nausea, fever Abdominal pain
80/54
2014
Saudi Arabia
24/F
81/55
2014/2015
Saudi Arabia
82/56
/2015
83 /57
2015
USA (Arizona) Iran
84/58
2015
85 /59
SC
RI PT
72/49
Histopahology/Culture /(B.ranarum) from liver Histopahology/Culture (B.ranarum) Histopathology/Culture negative
R
Histopathology
Ce, C
Histopathology/Culture positive (Basidiobolus spp.)
I;C I; Ce; L
NR/Yes/Yes
C
Histopathology
7,070 µL/14,6%/Yes
L; C; P
36/M
Abdominal pain, nausea, vomiting, abdominal distension, constipation Suspected appendicitis
16,000 µL/18%/Yes
Ce
Histopathology/Culture & PCR positive (B. ranarum) Histopathology
56/M
Abdominal pain, rectal pain
NR/NR/NR
Ce; R
Histopathology
2/F
Abdominal pain
11-12,000 µL/25-35%/Yes
L
Histopathology
Qatar
4/F
Abdominal pain, rectal bleeding, weight loss,
NR/NR/Yes
C
Histopathology
NR/2016
India
44/M
Liver transplant patient; rise in transaminases
NR/NR/NR
L
Culture (B. ranarum) of liver aspirate
86/60
NR/2017
Saudi Arabia
7/M
Abdominal pain, rectal bleeding, weight loss, fever
10,030 µL/15.9%/Yes
R
Histopathology
87/61
NR/2017
Saudi Arabia
7/F
19,000 µL(3000)/Yes
C;R
Histopathology
88/62
NR/2017
Iran
5/M
Abdominal pain, constipation, fever, palpable mass Abdominal pain, fever, anorexia, weight loss, vomiting
23,900 µL/11%/Yes
Ce; C; I
Histopathology/Culture (Basidiobolus spp.)
AC C
EP
TE D
M AN U 14,300 µL/12%/Yes
Histopathology /PCR (B. ranarum) Histopathology
then itraconazole (12 months) Surgery/Itracona zole (7 months) Surgery Surgery/Voricon azole (12 months) Drainage/Terbin afine+voriconaz ole (12 months) Surgery/LAmB+ posaconazole then voriconazole (4 months) Antituberculous treatment Surgery/Itracona zole (4 months) Voriconazole (12 months)
Voriconazole
Surgery/Itracona zole (4 months); voriconazole Itraconazole (12 months) Surgery/AmB (1 month) Surgery/Voricon azole (12 months) LAmB; itraconazole, caspofungin, posaconazole Surgery/Voricon azole (12 months) Voriconazole (9 months) Amphotericin B (2 months); posaconazole (6 months)
Alive (7 months) Death Alive (12 months) Alive (12 months) Alive (4 months)
Death (2 months) Alive (12 months) Alive (12 months after discontinuing therapy) Alive (2 months) Alive
Alive (12 months) Alive (9 months) Alive (12 months) Death (MOF and bacterial sepsis) Alive (12 months) Alive (10 months) Alive (6 months)
6
ACCEPTED MANUSCRIPT
89/ PR
2013/2018
Italy/Ireland
25/M
Abdominal pain
10,100 µL/10%/Yes
I; Ce; C
Histopathology/PCR (B.ranarum)
Surgery/Itracona zole (8 months)
Alive (13 months)
AC C
EP
TE D
M AN U
SC
RI PT
Twelve patients reported with no details in the review by Vikram et al. are not described in the table. D, duodenum; E, esophagus; S, stomach; I, ileum; Ce, cecum; C, colon; R, rectum; O, oropharynx; BT, biliary tract; L, liver; P, peritoneum; M, mesentery; AmB, amphotericin B; LAmB, liposomal amphotericin B
7
ACCEPTED MANUSCRIPT
23 (22.5%) 17 (16.7%) 41 (40.2%) 34 (33.3%) 14 (13.7%) 16 (15.7%) 15 (14.7%)
1 (1.7%)
6 (5.9%)
43/47 (91.5%)
69/81 (85.2%)
-
8/16 (50%)
EP
6 (10.3%) 3 (5.2%) 27 (46.5%) 22 (37.9%) 7 (12.1%) 10 (17.2%) 9 (15.5%)
AC C
Constipation 17 (39%) Abdominal distension 14 (32%) Fever 14 (32%) Weight loss 12 (27%) Diarrhea 7 (16%) Vomiting 6 (14%) Lower gastrointestinal 6 (14%) bleeding Hepatomegaly 5 (11%) Laboratory test results* Peripheral blood 26/34 (76%) eosinophilia Positive Basidiobolus 8/16 (50%) serology
TE D
M AN U
SC
RI PT
Table 3. Clinical manifestations, laboratory studies , sites of involvement and preliminary diagnosis in 102 patients with gastrointestinal basidiobolomycosis Patients, proportion Total Patients, proportion Characteristic (%)- Present review (%) –Review by Vikram (1964-2008)21 (2009-2017) 44 (43.1%) 58 (56.9%) 102 Number of pts Age, years, median 37.3 (2-81) 17.5 (1.1-77) 19 (1.1-81) Male sex 36 (81.8%) 40 (68.9%) 76 (74.5%) Country of residence Brazil 4 (9%) 4 (3.9 %) Iran 4 (9%) 17 (29.3%) 21(20.6%) Iraq 6 (10.3%) 6 (5.9%) Saudi Arabia 11 (25%) 27 (46.5%) 38 (37.2%) USA 19 (43%) 3 (5.2 %) 22 (21.6%) Other 6 (13.6%) # 5 (8.6 %)§ 11 (10.8%) Signs and symptoms Abdominal pain 37 (84%) 51 (87.9%) 88 (86.3%) Abdominal mass 19 (43%) 31 (30.4%) 12 (20.7%)
8
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AC C
EP
TE D
M AN U
SC
RI PT
Growth of 17/24 (71%) 17/29 (58.6%) 34/53 (64.2%) Basidiobolus in culture 43/44 (98%) 57/57 (100%) 100/101 (99%) Characteristic histopathology Organ involvement Stomach 6 (14%) 2 (3.5%) 8 (7.9%) Small bowel 16 (36%) 16 (28.1%) 32 (31.7%) Colon/rectum 36 (82%) 50 (87.7%) 85 (84.2%) Liver/gallbladder 13 (30%) 10 (17.5%) 22 (21.8%) Pancreas 3 (5.3%) 3 (2.9%) Preliminary diagnosis Malignancy 19 (43%) 6 (10.9%) 25 (24.7%) Inflammatory bowel 7 (16%) 6 (10.9%) 13 (12.9%) disease Diverticulitis 5 (11%) 5 (4.9%) Appendicitis 3 (7%) 5 (9.1%) 8 (7.9%) Lymphoma 2 (5%) 4 (7.3%) 6 (5.9%) Gastrointestinal 2 (5%) 3 (5.5%) 5 (4.9%) tuberculosis Ameboma 1 (1.8%) 1 (0.9%) Schistosomiasis 1 (1.8%) 1 (0.9%) Other 4 (9%) 4 (3.9%) Antifungal treatment 37/43 (86%) 56/58 (96.5%) 93/101 (92.1%) Itraconazole 26/37 (70.3%) 24/56 (42.9%) 50/93 (53.8%) 2/56 (3.6%) 10/93 (10.7%) Amphotericin B 8/37 (21.6%) 10/56 (17.9%)** 12/93 (12.9%) Voriconazole 2/37 (5.4%) Posaconazole 0/37 (0%) 2/56 (3.6%) 2/93 (2.2%) Amphotericin B plus 3/37 (8.1%) 18/56 (32.1%) 21/93 (22.6%) (or followed by azole) 8 (18%) died 11 (18.9%) died 19 (18.6%) died Outcome * Laboratory data are reported only when available. # One patient each from :Nigeria, India, Bangladesh, Italy, The Netherlands; for 1 country was unknown; § One patient each from: India, Ireland, Mali, Oman, Qatar: ** In one case associated with terbinafine 9
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
B
EP AC C
C
TE D
M AN U
SC
RI PT
A
D
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
3
EP
1
AC C
3
1
TE D
67
22
4